Table of Contents Author Guidelines Submit a Manuscript
Journal of Diabetes Research
Volume 2016 (2016), Article ID 1540267, 8 pages
http://dx.doi.org/10.1155/2016/1540267
Review Article

Physiological and Pharmacological Roles of FGF21 in Cardiovascular Diseases

Peng Cheng,1,2,3 Fangfang Zhang,1,2,3 Lechu Yu,1 Xiufei Lin,1,2,3 Luqing He,1,2,3 Xiaokun Li,2,3 Xuemian Lu,1 Xiaoqing Yan,1,2,3 Yi Tan,1,2,4 and Chi Zhang1,2,3

1The Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical University, Wenzhou 325035, China
2Ruian Center of the Chinese-American Research Institute for Diabetic Complications, The Third Affiliated Hospital, Wenzhou Medical University, Wenzhou 325200, China
3School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
4Kosair Children Hospital Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY 40202, USA

Received 26 October 2015; Revised 26 February 2016; Accepted 18 April 2016

Academic Editor: Raffaella Mastrocola

Copyright © 2016 Peng Cheng et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Cardiovascular disease (CVD) is one of the most severe diseases in clinics. Fibroblast growth factor 21 (FGF21) is regarded as an important metabolic regulator playing a therapeutic role in diabetes and its complications. The heart is a key target as well as a source of FGF21 which is involved in heart development and also induces beneficial effects in CVDs. Our review is to clarify the roles of FGF21 in CVDs. Strong evidence showed that the development of CVDs including atherosclerosis, coronary heart disease, myocardial ischemia, cardiac hypertrophy, and diabetic cardiomyopathy is associated with serum FGF21 levels increase which was regarded as a compensatory response to induced cardiac protection. Furthermore, administration of FGF21 suppressed the above CVDs. Mechanistic studies revealed that FGF21 induced cardiac protection likely by preventing cardiac lipotoxicity and the associated oxidative stress, inflammation, and apoptosis. Normally, FGF21 induced therapeutic effects against CVDs via activation of the above kinases-mediated pathways by directly binding to the FGF receptors of the heart in the presence of β-klotho. However, recently, growing evidence showed that FGF21 induced beneficial effects on peripheral organs through an indirect way mediated by adiponectin. Therefore whether adiponectin is also involved in FGF21-induced cardiac protection still needs further investigation.

1. Introduction

Cardiovascular diseases (CVDs) are the leading cause of death worldwide composed of heart and blood vessel diseases. In the recent years, the incidence of CVDs has been increasing at a sharp rate globally. According to the World Health Report 2010, CVDs contributed to 17.5 million deaths and these numbers are estimated to increase to 23.3 million by 2030 [1, 2].

Fibroblast growth factor (FGF) is a cytokine superfamily with pleiotropic biological functions including regulating cell growth, differentiation, development, and metabolism [37]. Human FGFs contain 22 members which can be divided into 7 subfamilies based on phylogeny and sequence [810]. Due to the lack of a heparin binding domain, FGF19 subfamily members (FGF19, FGF21, and FGF23) function in an endocrine manner rather than an autocrine manner as other subfamily members of FGFs [9]. Among them, FGF21 is a polypeptide with 209/210 (human/rodent) amino acid residues that is primarily produced and secreted by the liver, adipose tissue, and thymus [11]. FGF21 expression is mainly regulated by peroxisome proliferator-activated receptor α (PPARα) in the liver [12] and PPARγ in adipocytes [13, 14]. FGF21 was firstly cloned in 2000 [11] and received global attention in recent years due to its outstanding ability on regulating carbohydrate and lipid metabolism including improving insulin sensitivity, lowering blood glucose, reducing hepatic/plasma triglycerides, inducing weight loss by increasing energy expenditure, and reducing fat mass [1518]. Further studies indicated that FGF21 functions by binding to (FGFR)1c and (FGFR)2c in the presence of coreceptor β-klotho and activation of downstream signaling pathway [19, 20]. Although FGF21 and other members of FGFs share the same FGF receptors, the coreceptors are different (β-klotho for FGF21 and heparin for others) which determined that they have different bioactivity due to activation of various pathways [21, 22]. Unlike traditional insulin therapy in clinics, FGF21 did not cause hypoglycemia [16]. The possible explanation is that FGF21 induces physiological role in healthy condition and pharmacological role under unhealthy condition [23, 24]. Additionally, FGF21 does not lead to carcinogenic event due to lack of mitogenic function which makes it possible to be administrated in vivo in clinics [16]. Therefore, FGF21 may hold promise as a clinically therapeutic option due to the abovementioned characters and advantages.

In recent clinical and preclinical studies, CVDs have been closely associated with serum FGF21 which increased in the patients with atherosclerosis, coronary heart disease, myocardial ischemia, cardiac hypertrophy, and diabetic cardiomyopathy [2527]. Therefore FGF21 has the potential to be considered as a biomarker for the above CVDs.

Whether the increased serum FGF21 level is the basis for CVD pathogenesis or is induced to protect the heart form CVDs is still under discussion. However, growing evidence indicated that administration of exogenous FGF21 induces preventive effects on most of the above CVDs, suggesting that FGF21 not only is a simple marker of cardiovascular risk but also induces a protective effect on the cardiovascular system contributing to a reduction in risk (Table 1). In clinics, serum FGF21 levels were increased in patients with obesity or type 2 diabetes which was associated with high risk of CVDs. The paradoxical phenomenon was supposed to be explained by a compensatory response to induce cardiac protection or resistance to FGF21 which impaired its bioactivity [28, 29]. In animal study, we found that at the early-stage of diabetes serum FGF21 level of mice was sharply increased compared with nondiabetic mice (C57BL/6J), while it was dramatically decreased at the late-stage of diabetes which further confirmed that early-stage increase of serum FGF21 was a compensatory response and induced beneficial effect on the heart; late-stage decrease may be the cause of diabetes-induced cardiac damage [30], since the above CVDs are always attributed to lipid metabolic disorder. Mechanistic studies indicated that FGF21-induced cardiac protection in CVDs is possibly attributed to the suppression of lipotoxicity since the above CVDs are always the consequences of lipotoxicity. This review tries to illuminate the underlying relationship between FGF21 and CVDs and the possible mechanisms.

Table 1: Summary of major pharmacological studies of FGF21 in heart disease.

2. FGF21 and Atherosclerosis and Coronary Heart Disease

Atherosclerosis is a chronic, inflammatory disorder characterized by the deposition of excess lipids in the arterial intima [31]. The accrued evidence indicated that lipid-lowering therapy limits the progression of atherosclerosis and reduces CAD events [32]. Since FGF21 plays an important role in the regulation of lipid metabolism, the effect of FGF21 in atherosclerosis is of interest. Clinical studies showed that increased circulating FGF21 levels were discovered in atherosclerotic patients or the individuals with high risk of developing atherosclerosis [33, 34]. Additionally, an in vivo study demonstrated that increased serum FGF21 was observed in aortas of apoE−/− mice (C57BL/6J background) [35]. Strong evidence identified that administration of exogenous FGF21 significantly improved lipid metabolic disorders and reduced atherosclerotic plaque areas in these animals [36]. Moreover, Lin et al. also reported that FGF21 deficiency enhanced atherosclerotic deterioration and mortality in apoE−/− mice (C57BL/6J background) [35], implying that increased serum FGF21 in patients with atherosclerosis described previously induces beneficial effect rather than the basic for atherosclerotic pathogenesis. Mechanistic study indicated that FGF21-induced prevention of atherosclerosis was associated with suppression of endoplasmic reticulum stress-mediated apoptosis in apoE−/− mice (C57BL/6J background) [37]. Further mechanistic studies revealed that prevention of atherosclerosis by FGF21 was attributed to the fine-tuning of multiorgan cross talk among the liver, adipose tissue, and blood vessels, characterized by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice with atherosclerosis [35]. Although FGF21 functions in an endocrine manner, whether FGF21 can also induce a direct protection to the blood vessels remains unclear. For decades, lowering levels of low-density lipoprotein (LDL) cholesterol and increasing level of high-density lipoprotein (HDL) have formed the cornerstone of management of patients with atherosclerotic cardiovascular disease. Strong evidence demonstrated that FGF-21 dramatically improved the condition of atherosclerosis in Wistar rats by decreasing serum LDL levels and increasing serum HDL levels. Moreover, FGF-21-induced antioxidative function is also involved in its therapeutic effect in atherosclerotic Wistar rat characterized by increased levels of superoxide dismutase, reduced glutathione, and reduced malondialdehyde [38].

Along with the development of atherosclerosis, the artery’s lining becomes hardened, stiffened, and swollen with all sorts of “gunge,” including fatty deposits and abnormal inflammatory cells, to form a plaque and then eventually deteriorate into coronary heart disease [3941]. Strong evidence indicated that cardiac endothelial cell dysfunction may be an early initiating factor for atherosclerosis which facilitates the development of coronary heart disease [42]. Oxidized LDL (ox-LDL) is a proatherogenic lipoprotein that accumulates in the vascular wall and contributes to vascular dysfunction at the early-stage of atherosclerosis development [4353]. Enhanced serum ox-LDL and antibodies against its epitopes are predictive for endothelial dysfunction and subsequent coronary heart disease [43]. Previous in vitro study indicated that both FGF21 mRNA and protein expressions were increased in response to ox-LDL treatment in cardiac endothelial cells and this was protective against apoptosis caused by ox-LDL [54]. Also, FGF21 has been reported to prevent high glucose induced cell damage and endothelial nitric oxide synthase dysfunction through an AMP-activated protein kinase- (AMPK-) dependent pathway in endothelial cells [55]. Therefore the relationship between FGF21 and coronary heart disease is of interest. Shen et al. reported that serum FGF21 level was positively associated with coronary heart disease in clinics [56, 57]. Our previous work confirmed that serum levels of FGF-21 are increased in patients with coronary heart disease independently associated with adverse lipid profiles [33]. In contrast, another study indicated that serum FGF21 has been associated with hypertriglyceridemia, hyperinsulinemia, and pericardial fat accumulation but not associated with coronary heart disease [58]. This paradox may be explained by decreased body mass index of healthy controls compared to patients with coronary heart diseases.

3. FGF21 and Myocardial Ischemia

Myocardial ischemia, a disorder causing cardiomyocytes injury and myocardial infarction and malfunction, activates adaptive responses enhancing myocardial tolerance to ischemia. Liu et al. indicated that, in response to myocardial ischemia in the C57BL/6J mouse, liver- and adipocytes-derived FGF21 was upregulated and secreted into the circulation. After interacting with FGFR1 in cardiomyocytes in the presence of β-klotho, FGF21 activates its downstream kinases and proteins including phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB/AKT), and Bcl2 antagonist of cell death (BAD), thereby reducing myocardial ischemia-induced apoptosis characterized by reduction of caspase-3 activity [59]. However, the adaptive response was not found in FGF21-deficient mice. Reversely, myocardial ischemic size was significantly smaller in FGF21 transgenic mice than that in wild type mice [59], suggesting that upregulated endogenous FGF21 derived from the liver and adipose tissue in response to myocardial injury induced cardiac protection mediated by activation of FGFR1/β-klotho-PI3K-Akt1-BAD signaling pathway. Although various growth factors and cytokines were upregulated during myocardial ischemia, the expression and secretion of cardiac FGF21 had no alteration, implying FGF21 induces cardiac protection against myocardial ischemia in an endocrine rather than an autocrine manner [59, 60]. To date, a question of whether administration of exogenous FGF21 can also induce cardiac protection during myocardial ischemia and if so whether the protection of exogenous FGF21 against myocardial ischemia can be direct to the heart or cardiomyocytes appears. This question was answered by Patel group [61]. They found that administration of exogenous FGF21 induced significant cardioprotection and restored cardiac function following global ischemia in Langendorff perfused rat hearts. Further study revealed that inhibition of AKT, extracellular signal-regulated kinase (ERK1/2), and AMPK impaired FGF21-induced antimyocardial ischemia effect in the hearts of obese Wistar rats, suggesting that the above kinases are involved in this cardioprotection of FGF21 [61]. Our previous in vitro study also confirmed that administration of exogenous FGF-21 attenuated ischemia-reperfusion induced damage in H9c2 cells characterized by inhibition of oxidative stress and apoptosis [62]. The mechanistic study revealed that FGF21-induced protection against ischemia-reperfusion injury in cardiac cells mainly depended on the activation of Akt-GSK-3β-caspase-3 signaling pathway by preventing oxidative stress and recovery of the energy supply [62].

4. FGF21 and Cardiac Hypertrophy

Hypertrophic remodeling characterized by enlarged cardiomyocytes is an adaptive response of the heart to certain stresses. And it is also the leading cause of multiple cardiovascular problems including hypertension, myocardial ischemia, valvular disease, and cardiomyopathy [6769]. Mature cardiomyocytes are considered to be terminally differentiated cells with no regenerative ability [7072]. Under stresses, cardiac hypertrophy is characterized by cardiomyocytes enlargement, rather than cells division [73, 74], and this phenomenon is accompanied by the increase of extracellular matrix and fibroblasts inside the heart [75, 76].

Recently, cardiac hypertrophy was reported to induce FGF21 gene expression in the cardiomyocytes of mouse, and this was subjected to transcriptional regulation of the hepatic silent mating type information regulation 2 homolog 1/PPARα pathway [64]. In turn, FGF21 knockout mice had greater heart weights and more severe cardiac dysfunction in response to isoproterenol infusion along with induction of hypertrophic inflammatory markers [64]. However, administration of recombinant FGF21 significantly prevented isoproterenol-induced cardiac hypertrophy damage in mice [64]. Mechanistic studies indicated that FGF21 prevented cardiac hypertrophy by activating mitogen-activated protein kinase (MAPK) signaling via activation of FGFR1c/β-klotho [64, 77]. Additionally, FGF21 prevented cardiac hypertrophy by promoting multiple antioxidant genes expressions (e.g., uncoupling proteins 2 and 3, also superoxide dismutase-2) and inhibiting the formation of reactive oxygen species in an autocrine manner [65].

5. FGF21 and Diabetic Cardiomyopathy

Diabetic patients develop the diabetic cardiomyopathy independent of coronary artery disease and hypertension [78, 79]. Diabetic cardiomyopathy is attributed to multiple pathogenic factors, including hyperglycemia, hyperlipidemia, and inflammation [8082]. Cardiomyopathy is a late consequence of diabetes-induced early cardiac responses especially the myocardial apoptosis [83, 84]. Thus, treatments to reduce cardiac apoptosis may help control diabetic cardiomyopathy.

Recently, we reported that cardiac FGF21 mRNA expression was positively associated with the development of diabetes in the type 1 diabetic mice, suggesting that the increased cardiac FGF21 expression may be beneficial to the heart in this regard [30]. In the study we also observed cardiac apoptosis in early diabetic mice, which was remarkably prevented by administration of recombinant FGF21 [30]. Similar protection by FGF21 was observed in mice with cardiac lipotoxicity induced by fatty-acid [30]. Mechanistic studies indicated that FGF21-induced antiapoptotic effects in vitro and in vivo were mediated by ERK1/2-p38-MAPK-AMPK signaling pathway [30]. Thus, FGF21-induced cardioprotection in diabetic mice is mainly attributed to prevention of lipotoxicity by FGF21. Also, long-term treatment of FGF21 prevented diabetic-induced cardiac dysfunction and fibrosis mediated by the same signaling pathway as above [30]. Our work also revealed that FGF21 deletion-aggravated cardiac lipid accumulation is likely mediated by cardiac Nrf2-driven CD36 upregulation in type 1 diabetic mice, which contributes to increased cardiac oxidative stress and remodeling, and eventual development of diabetic cardiomyopathy [66].

6. Summary

CVD includes atherosclerosis, coronary heart disease, myocardial ischemia, cardiac hypertrophy, and diabetic cardiomyopathy which are all closely associated with severe lipid metabolic disorders [8587]. FGF21, a metabolic regulator of carbohydrates and lipids, has been shown to improve insulin sensitivity and glucose uptake and suppress lipogenesis and lipid oxidation [1518]. Clinical studies indicated that serum FGF21 changes were positively associated with the development of atherosclerosis, coronary heart disease, myocardial ischemia, cardiac hypertrophy, and diabetic cardiomyopathy, which implies that upregulated endogenous FGF21 may improve CVDs. Specifically, FGF21 prevented atherosclerosis and subsequent coronary heart disease was attributed to multiorgan cross talk among the liver, adipose tissue, and blood vessels and was characterized by suppression of lipid accumulation and increased lipid oxidation [63]. Similarly, FGF21 prevented stress-induced CH via enhancing lipid oxidation mediated by the ERK1/2-CREB-PGC-1α signaling pathway [64]. FGF21 also prevented myocardial ischemia and diabetic cardiomyopathy via Akt- or AMPK-mediated signaling pathways which regulate lipid and glucose metabolisms (Figure 1). Since serum FGF21 increases in several kinds of CVDs, serum FGF21 levels might be regarded as a potential biomarker not only for diagnosis of metabolic disorders but also for diagnosis of CVD in clinics. And supplementation of exogenous FGF21 might also induce beneficial effect in patients with CVD based on the conclusion of preclinical studies.

Figure 1: FGF21 induces preventive effect on CVDs through multiple signaling pathways. As a classical cytokine, FGF21 functions as a metabolic regulator by binding with its receptor FGFR1 or FGFR2 in the presence of β-klotho. Growing studies demonstrated that FGF21 also induced beneficial effects on CVDs probably due to inhibition of glucose or lipid metabolic disorders. For instance, FGF21 prevented atherosclerosis and the subsequent CHD by inhibition of lipogenesis which was also the possible mechanism of FGF21-induced preventive effect on CH. Additionally, FGF21 also prevented MI and DC by activation of Akt- and AMPK-mediated signaling pathway which were usually involved in maintaining glucose and lipid homeostasis.

Disclosure

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.

Competing Interests

The authors declare that there are no competing interests regarding the publication of this paper.

Authors’ Contributions

Peng Cheng, Fangfang Zhang, and Lechu Yu are equal contributors to the review.

Acknowledgments

This study was supported in part by grants from the National Science Foundation of China (81370917, to Chi Zhang; 81471045, to Xuemian Lu; 81573435, 81273509, and 30971209 to Yi Tan), the Research Development Fund of Wenzhou Medical University (QTJ13005, to Chi Zhang; QTJ13007 to Yi Tan), the Medical and Healthy Technological Grant of Zhejiang Province (201472233, to Chi Zhang), the Project of Public Welfare of Wenzhou (2014Y0416, to Chi Zhang), and the Project for Selected Overseas Chinese Supported by Zhejiang Technology Foundation (to Chi Zhang) and the Key New Drug Development Grant 2012ZX09103-301-016 (to Xiaokun Li and Yi Tan) and the grants from the American Diabetes Association and Juvenile Diabetes Research Foundation (1-13-JF-53 and 1-INO-2014-122-A-N to Yi Tan).

References

  1. Y. Yang, W. Duan, Y. Li et al., “Novel role of silent information regulator 1 in myocardial ischemia,” Circulation, vol. 128, no. 20, pp. 2232–2240, 2013. View at Publisher · View at Google Scholar · View at Scopus
  2. C. D. Mathers and D. Loncar, “Projections of global mortality and burden of disease from 2002 to 2030,” PLoS Medicine, vol. 3, no. 11, pp. 2011–2030, 2006. View at Publisher · View at Google Scholar · View at Scopus
  3. W. H. Burgess and T. Maciag, “The heparin-binding (fibroblast) growth factor family of proteins,” Annual Review of Biochemistry, vol. 58, pp. 575–606, 1989. View at Publisher · View at Google Scholar · View at Scopus
  4. D. B. Rifkin and D. Moscatelli, “Recent developments in the cell biology of basic fibroblast growth factor,” The Journal of Cell Biology, vol. 109, no. 1, pp. 1–6, 1989. View at Publisher · View at Google Scholar · View at Scopus
  5. T. P. Yamaguchi and J. Rossant, “Fibroblast growth factors in mammalian development,” Current Opinion in Genetics & Development, vol. 5, no. 4, pp. 485–491, 1995. View at Publisher · View at Google Scholar · View at Scopus
  6. F. Guillemot and C. Zimmer, “From cradle to grave: the multiple roles of fibroblast growth factors in neural development,” Neuron, vol. 71, no. 4, pp. 574–588, 2011. View at Publisher · View at Google Scholar · View at Scopus
  7. M. Goldfarb, “Fibroblast growth factor homologous factors: evolution, structure, and function,” Cytokine and Growth Factor Reviews, vol. 16, no. 2, pp. 215–220, 2005. View at Publisher · View at Google Scholar · View at Scopus
  8. K. H. Bae, J. G. Kim, and K. G. Park, “Transcriptional regulation of fibroblast growth factor 21 expression,” Endocrinology and Metabolism, vol. 29, no. 2, pp. 105–111, 2014. View at Publisher · View at Google Scholar
  9. N. Itoh and D. M. Ornitz, “Evolution of the Fgf and Fgfr gene families,” Trends in Genetics, vol. 20, no. 11, pp. 563–569, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. W. L. McKeehan, F. Wang, and M. Kan, “The heparan sulfate-fibroblast growth factor family: diversity of structure and function,” Progress in Nucleic Acid Research and Molecular Biology, vol. 59, pp. 135–176, 1998. View at Google Scholar · View at Scopus
  11. T. Nishimura, Y. Nakatake, M. Konishi, and N. Itoh, “Identification of a novel FGF, FGF-21, preferentially expressed in the liver,” Biochimica et Biophysica Acta (BBA)—Gene Structure and Expression, vol. 1492, no. 1, pp. 203–206, 2000. View at Publisher · View at Google Scholar · View at Scopus
  12. T. Inagaki, P. Dutchak, G. Zhao et al., “Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21,” Cell Metabolism, vol. 5, no. 6, pp. 415–425, 2007. View at Publisher · View at Google Scholar · View at Scopus
  13. E. S. Muise, B. Azzolina, D. W. Kuo et al., “Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor γ and altered metabolic states,” Molecular Pharmacology, vol. 74, no. 2, pp. 403–412, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. H. Wang, L. Qiang, and S. R. Farmer, “Identification of a domain within peroxisome proliferator-activated receptor γ regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes,” Molecular and Cellular Biology, vol. 28, no. 1, pp. 188–200, 2008. View at Publisher · View at Google Scholar · View at Scopus
  15. H. Kurosu, M. Choi, Y. Ogawa et al., “Tissue-specific expression of βklotho and Fibroblast Growth Factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21,” The Journal of Biological Chemistry, vol. 282, no. 37, pp. 26687–26695, 2007. View at Publisher · View at Google Scholar · View at Scopus
  16. A. Kharitonenkov, T. L. Shiyanova, A. Koester et al., “FGF-21 as a novel metabolic regulator,” The Journal of Clinical Investigation, vol. 115, no. 6, pp. 1627–1635, 2005. View at Publisher · View at Google Scholar · View at Scopus
  17. A. Kharitonenkov, J. D. Dunbar, H. A. Bina et al., “FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho,” Journal of Cellular Physiology, vol. 215, no. 1, pp. 1–7, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. J. Xu, S. Stanislaus, N. Chinookoswong et al., “Acute glucose-lowering and insulin-sensitizing action of FGF21 in insulin-resistant mouse models—association with liver and adipose tissue effects,” American Journal of Physiology—Endocrinology and Metabolism, vol. 297, no. 5, pp. E1105–E1114, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. J. Yie, W. Wang, L. Deng et al., “Understanding the physical interactions in the FGF21/FGFR/β-Klotho complex: structural requirements and implications in FGF21 signaling,” Chemical Biology and Drug Design, vol. 79, no. 4, pp. 398–410, 2012. View at Publisher · View at Google Scholar · View at Scopus
  20. A. Kharitonenkov and A. C. Adams, “Inventing new medicines: the FGF21 story,” Molecular Metabolism, vol. 3, no. 3, pp. 221–229, 2014. View at Publisher · View at Google Scholar · View at Scopus
  21. M. Suzuki, Y. Uehara, K. Motomura-Matsuzaka et al., “βKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c,” Molecular Endocrinology, vol. 22, no. 4, pp. 1006–1014, 2008. View at Publisher · View at Google Scholar · View at Scopus
  22. I. Urakawa, Y. Yamazaki, T. Shimada et al., “Klotho converts canonical FGF receptor into a specific receptor for FGF23,” Nature, vol. 444, no. 7120, pp. 770–774, 2006. View at Publisher · View at Google Scholar · View at Scopus
  23. H. Li, J. Zhang, and W. Jia, “Fibroblast growth factor 21: a novel metabolic regulator from pharmacology to physiology,” Frontiers of Medicine, vol. 7, no. 1, pp. 25–30, 2013. View at Publisher · View at Google Scholar · View at Scopus
  24. S. A. Kliewer and D. J. Mangelsdorf, “Fibroblast growth factor 21: from pharmacology to physiology,” The American Journal of Clinical Nutrition, vol. 91, no. 1, pp. 254S–257S, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. T. Kotulak, J. Drapalova, P. Kopecky et al., “Increased circulating and epicardial adipose tissue mRNA expression of fibroblast growth factor-21 after cardiac surgery: possible role in postoperative inflammatory response and insulin resistance,” Physiological Research/Academia Scientiarum Bohemoslovaca, vol. 60, pp. 757–767, 2011. View at Google Scholar
  26. K. I. Stanford, R. J. W. Middelbeek, K. L. Townsend et al., “Brown adipose tissue regulates glucose homeostasis and insulin sensitivity,” The Journal of Clinical Investigation, vol. 123, no. 1, pp. 215–223, 2013. View at Publisher · View at Google Scholar · View at Scopus
  27. F. G. Schaap, A. E. Kremer, W. H. Lamers, P. L. M. Jansen, and I. C. Gaemers, “Fibroblast growth factor 21 is induced by endoplasmic reticulum stress,” Biochimie, vol. 95, no. 4, pp. 692–699, 2013. View at Publisher · View at Google Scholar · View at Scopus
  28. X. Zhang, D. C. Y. Yeung, M. Karpisek et al., “Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans,” Diabetes, vol. 57, no. 5, pp. 1246–1253, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. Y. Xiao, L. Liu, A. Xu et al., “Serum fibroblast growth factor 21 levels are related to subclinical atherosclerosis in patients with type 2 diabetes,” Cardiovascular Diabetology, vol. 14, article 72, 2015. View at Publisher · View at Google Scholar · View at Scopus
  30. C. Zhang, Z. Huang, J. Gu et al., “Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signalling pathway,” Diabetologia, vol. 58, no. 8, pp. 1937–1948, 2015. View at Publisher · View at Google Scholar · View at Scopus
  31. A. J. Lusis, “Atherosclerosis,” Nature, vol. 407, no. 6801, pp. 233–241, 2000. View at Publisher · View at Google Scholar · View at Scopus
  32. J. Davignon, “Advances in lipid-lowering therapy in atherosclerosis,” Advances in Experimental Medicine and Biology, vol. 498, pp. 49–58, 2001. View at Publisher · View at Google Scholar · View at Scopus
  33. Z. Lin, Z. Wu, X. Yin et al., “Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile,” PLoS ONE, vol. 5, no. 12, Article ID e15534, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. W. S. Chow, A. Xu, Y. C. Woo et al., “Serum fibroblast growth factor-21 levels are associated with carotid atherosclerosis independent of established cardiovascular risk factors,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 33, no. 10, pp. 2454–2459, 2013. View at Publisher · View at Google Scholar · View at Scopus
  35. Z. Lin, X. Pan, F. Wu et al., “Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice,” Circulation, vol. 131, no. 21, pp. 1861–1871, 2015. View at Publisher · View at Google Scholar · View at Scopus
  36. X. Wu, Y. Lyu, K. Fu et al., “Impact of exogenous fibroblast growth factor 21 on atherosclerosis in apolipoprotein E deficient mice,” Zhonghua Xin Xue Guan Bing Za Zhi, vol. 42, no. 2, pp. 126–131, 2014. View at Publisher · View at Google Scholar · View at Scopus
  37. X. Wu, Y.-F. Qi, J.-R. Chang et al., “Possible role of fibroblast growth factor 21 on atherosclerosis via amelioration of endoplasmic reticulum stress-mediated apoptosis in apoE−/− mice,” Heart and Vessels, vol. 30, no. 5, pp. 657–668, 2015. View at Publisher · View at Google Scholar
  38. W. Zhu, C. Wang, L. Liu et al., “Effects of fibroblast growth factor 21 on cell damage in vitro and atherosclerosis in vivo,” Canadian Journal of Physiology and Pharmacology, vol. 92, no. 11, pp. 927–935, 2014. View at Publisher · View at Google Scholar · View at Scopus
  39. S. K. Bhatia, “Tissue engineering for clinical applications,” Biotechnology Journal, vol. 5, no. 12, pp. 1309–1323, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. D. P. Faxon, M. A. Creager, S. C. Smith Jr. et al., “Atherosclerotic vascular disease conference: executive summary: atherosclerotic vascular disease conference proceeding for healthcare professionals from a special writing group of the American Heart Association,” Circulation, vol. 109, no. 21, pp. 2595–2604, 2004. View at Publisher · View at Google Scholar · View at Scopus
  41. B. Akadam-Teker, O. Kurnaz, E. Coskunpinar et al., “The effects of age and gender on the relationship between HMGCR promoter-911 SNP (rs33761740) and serum lipids in patients with coronary heart disease,” Gene, vol. 528, no. 2, pp. 93–98, 2013. View at Publisher · View at Google Scholar · View at Scopus
  42. P. Rajendran, T. Rengarajan, J. Thangavel et al., “The vascular endothelium and human diseases,” International Journal of Biological Sciences, vol. 9, no. 10, pp. 1057–1069, 2013. View at Publisher · View at Google Scholar · View at Scopus
  43. J. Galle, T. Hansen-Hagge, C. Wanner, and S. Seibold, “Impact of oxidized low density lipoprotein on vascular cells,” Atherosclerosis, vol. 185, no. 2, pp. 219–226, 2006. View at Publisher · View at Google Scholar · View at Scopus
  44. M. T. Quinn, S. Parthasarathy, and D. Steinberg, “Lysophosphatidylcholine: a chemotactic factor for human monocytes and its potential role in atherogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 8, pp. 2805–2809, 1988. View at Publisher · View at Google Scholar · View at Scopus
  45. J. Frostegard, A. Haegerstrand, M. Gidlund, and J. Nilsson, “Biologically modified LDL increases the adhesive properties of endothelial cells,” Atherosclerosis, vol. 90, no. 2-3, pp. 119–126, 1991. View at Publisher · View at Google Scholar · View at Scopus
  46. S. Yui, T. Sasaki, A. Miyazaki, S. Horiuchi, and M. Yamazaki, “Induction of murine macrophage growth by modified LDLs,” Arteriosclerosis and Thrombosis, vol. 13, no. 3, pp. 331–337, 1993. View at Publisher · View at Google Scholar · View at Scopus
  47. V. Lindner, D. A. Lappi, A. Baird, R. A. Majack, and M. A. Reidy, “Role of basic fibroblast growth factor in vascular lesion formation,” Circulation Research, vol. 68, no. 1, pp. 106–113, 1991. View at Publisher · View at Google Scholar · View at Scopus
  48. S. Jimi, K. Saku, N. Uesugi, N. Sakata, and S. Takebayashi, “Oxidized low density lipoprotein stimulates collagen production in cultured arterial smooth muscle cells,” Atherosclerosis, vol. 116, no. 1, pp. 15–26, 1995. View at Publisher · View at Google Scholar · View at Scopus
  49. A. Loidl, R. Claus, E. Ingolic, H.-P. Deigner, and A. Hermetter, “Role of ceramide in activation of stress-associated MAP kinases by minimally modified LDL in vascular smooth muscle cells,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, vol. 1690, no. 2, pp. 150–158, 2004. View at Publisher · View at Google Scholar · View at Scopus
  50. M. Sata and K. Walsh, “Oxidized LDL activates fas-mediated endothelial cell apoptosis,” The Journal of Clinical Investigation, vol. 102, no. 9, pp. 1682–1689, 1998. View at Publisher · View at Google Scholar · View at Scopus
  51. S. J. Hardwick, L. Hegyi, K. Clare et al., “Apoptosis in human monocyte-macrophages exposed to oxidized low density lipoprotein,” The Journal of Pathology, vol. 179, no. 3, pp. 294–302, 1996. View at Publisher · View at Google Scholar · View at Scopus
  52. C. J. Schwartz, A. J. Valente, E. A. Sprague, J. L. Kelley, and R. M. Nerem, “The pathogenesis of atherosclerosis: an overview,” Clinical Cardiology, vol. 14, no. 2, pp. I-1–I-16, 1991. View at Google Scholar · View at Scopus
  53. L.-X. Li, J.-X. Chen, D.-F. Liao, and L. Yu, “Probucol inhibits oxidized-low density lipoprotein-induced adhesion of monocytes to endothelial cells by reducing P-selectin synthesis in vitro,” Endothelium: Journal of Endothelial Cell Research, vol. 6, no. 1, pp. 1–8, 1998. View at Google Scholar · View at Scopus
  54. Y. Lü, J.-H. Liu, L.-K. Zhang et al., “Fibroblast growth factor 21 as a possible endogenous factor inhibits apoptosis in cardiac endothelial cells,” Chinese Medical Journal, vol. 123, no. 23, pp. 3417–3421, 2010. View at Publisher · View at Google Scholar · View at Scopus
  55. M. Shao, X. Lu, W. Cong et al., “Multiple low-dose radiation prevents type 2 diabetes-induced renal damage through attenuation of dyslipidemia and insulin resistance and subsequent renal inflammation and oxidative stress,” PLoS ONE, vol. 9, no. 3, Article ID e92574, 2014. View at Publisher · View at Google Scholar · View at Scopus
  56. Y. Shen, X. Ma, J. Zhou et al., “Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease,” Cardiovascular Diabetology, vol. 12, article124, 2013. View at Publisher · View at Google Scholar · View at Scopus
  57. W. J. Kim, S. S. Kim, H. C. Lee et al., “Association between serum fibroblast growth factor 21 and coronary artery disease in patients with type 2 diabetes,” Journal of Korean medical science, vol. 30, no. 5, pp. 586–590, 2015. View at Google Scholar
  58. Y. Lee, S. Lim, E.-S. Hong et al., “Serum FGF21 concentration is associated with hypertriglyceridaemia, hyperinsulinaemia and pericardial fat accumulation, independently of obesity, but not with current coronary artery status,” Clinical Endocrinology, vol. 80, no. 1, pp. 57–64, 2014. View at Publisher · View at Google Scholar · View at Scopus
  59. S. Q. Liu, D. Roberts, A. Kharitonenkov et al., “Endocrine protection of ischemic myocardium by FGF21 from the liver and adipose tissue,” Scientific Reports, vol. 3, article 2767, 2013. View at Publisher · View at Google Scholar · View at Scopus
  60. S. Q. Liu, B. J. Tefft, D. T. Roberts et al., “Cardioprotective proteins upregulated in the liver in response to experimental myocardial ischemia,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 303, no. 12, pp. H1446–H1458, 2012. View at Publisher · View at Google Scholar · View at Scopus
  61. V. Patel, R. Adya, J. Chen et al., “Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts,” PLoS ONE, vol. 9, no. 2, Article ID e87102, 2014. View at Publisher · View at Google Scholar · View at Scopus
  62. W.-T. Cong, J. Ling, H.-S. Tian et al., “Proteomic study on the protective mechanism of fibroblast growth factor 21 to ischemia-reperfusion injury,” Canadian Journal of Physiology and Pharmacology, vol. 91, no. 11, pp. 973–984, 2013. View at Publisher · View at Google Scholar · View at Scopus
  63. Z. Lin, X. Pan, F. Wu et al., “Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice,” Circulation, vol. 131, no. 21, pp. 1861–1871, 2015. View at Publisher · View at Google Scholar · View at Scopus
  64. A. Planavila, I. Redondo, E. Hondares et al., “Fibroblast growth factor 21 protects against cardiac hypertrophy in mice,” Nature Communications, vol. 4, article 2019, 2013. View at Publisher · View at Google Scholar · View at Scopus
  65. A. Planavila, I. Redondo-Angulo, F. Ribas et al., “Fibroblast growth factor 21 protects the heart from oxidative stress,” Cardiovascular Research, vol. 106, no. 1, pp. 19–31, 2015. View at Publisher · View at Google Scholar · View at Scopus
  66. X. Yan, J. Chen, C. Zhang et al., “FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation,” Journal of Cellular and Molecular Medicine, vol. 19, no. 7, pp. 1557–1568, 2015. View at Publisher · View at Google Scholar · View at Scopus
  67. W. Nadruz, “Myocardial remodeling in hypertension,” Journal of Human Hypertension, vol. 29, no. 1, pp. 1–6, 2015. View at Publisher · View at Google Scholar · View at Scopus
  68. S. Yamamoto, S. Kita, T. Iyoda, T. Yamada, and T. Iwamoto, “New molecular mechanisms for cardiovascular disease: cardiac hypertrophy and cell-volume regulation,” Journal of Pharmacological Sciences, vol. 116, no. 4, pp. 343–349, 2011. View at Publisher · View at Google Scholar · View at Scopus
  69. S. P. Barry, S. M. Davidson, and P. A. Townsend, “Molecular regulation of cardiac hypertrophy,” The International Journal of Biochemistry & Cell Biology, vol. 40, no. 10, pp. 2023–2039, 2008. View at Publisher · View at Google Scholar · View at Scopus
  70. L. T. Shenje, P. Andersen, M. K. Halushka et al., “Mutations in Alstrom protein impair terminal differentiation of cardiomyocytes,” Nature Communications, vol. 5, article 3416, 2014. View at Publisher · View at Google Scholar
  71. J. Lovric, M. Mano, L. Zentilin, A. Eulalio, S. Zacchigna, and M. Giacca, “Terminal differentiation of cardiac and skeletal myocytes induces permissivity to AAV transduction by relieving inhibition imposed by DNA damage response proteins,” Molecular Therapy, vol. 20, no. 11, pp. 2087–2097, 2012. View at Publisher · View at Google Scholar · View at Scopus
  72. E. D. Frohlich and D. Susic, “Pressure overload,” Heart Failure Clinics, vol. 8, no. 1, pp. 21–32, 2012. View at Publisher · View at Google Scholar · View at Scopus
  73. D. Grove, R. Zak, K. G. Nair, and V. Aschenbrenner, “Biochemical correlates of cardiac hypertrophy. IV. Observations on the cellular organization of growth during myocardial hypertrophy in the rat,” Circulation Research, vol. 25, no. 4, pp. 473–485, 1969. View at Publisher · View at Google Scholar · View at Scopus
  74. D. Grove, K. G. Nair, and R. Zak, “Biochemical correlates of cardiac hypertrophy. 3. Changes in DNA content; the relative contributions of polyploidy and mitotic activity,” Circulation Research, vol. 25, no. 4, pp. 463–471, 1969. View at Publisher · View at Google Scholar · View at Scopus
  75. F. Simko, K. R. Bednarova, K. Krajcirovicova et al., “Melatonin reduces cardiac remodeling and improves survival in rats with isoproterenol-induced heart failure,” Journal of Pineal Research, vol. 57, no. 2, pp. 177–184, 2014. View at Publisher · View at Google Scholar · View at Scopus
  76. P. K. Gupta, D. J. DiPette, and S. C. Supowit, “Protective effect of resveratrol against pressure overload-induced heart failure,” Food Science & Nutrition, vol. 2, no. 3, pp. 218–229, 2014. View at Publisher · View at Google Scholar
  77. N. Itoh and H. Ohta, “Pathophysiological roles of FGF signaling in the heart,” Frontiers in Physiology, vol. 4, article 247, 2013. View at Publisher · View at Google Scholar · View at Scopus
  78. J. R. Sowers, M. Epstein, and E. D. Frohlich, “Diabetes, hypertension, and cardiovascular disease an update,” Hypertension, vol. 37, no. 4, pp. 1053–1059, 2001. View at Publisher · View at Google Scholar · View at Scopus
  79. S. Boudina and E. D. Abel, “Diabetic cardiomyopathy revisited,” Circulation, vol. 115, no. 25, pp. 3213–3223, 2007. View at Publisher · View at Google Scholar · View at Scopus
  80. H. Bugger and E. D. Abel, “Molecular mechanisms of diabetic cardiomyopathy,” Diabetologia, vol. 57, no. 4, pp. 660–671, 2014. View at Publisher · View at Google Scholar · View at Scopus
  81. S. Boudina and E. D. Abel, “Diabetic cardiomyopathy, causes and effects,” Reviews in Endocrine & Metabolic Disorders, vol. 11, no. 1, pp. 31–39, 2010. View at Publisher · View at Google Scholar · View at Scopus
  82. L. Cai and Y. J. Kang, “Oxidative stress and diabetic cardiomyopathy: a brief review,” Cardiovascular Toxicology, vol. 1, no. 3, pp. 181–193, 2001. View at Publisher · View at Google Scholar · View at Scopus
  83. E. Acar, D. Ural, U. Bildirici et al., “Diabetic cardiomyopathy,” The Anatolian Journal of Cardiology, vol. 11, pp. 732–737, 2011. View at Google Scholar
  84. L. Cai and Y. J. Kang, “Cell death and diabetic cardiomyopathy,” Cardiovascular Toxicology, vol. 3, no. 3, pp. 219–228, 2003. View at Publisher · View at Google Scholar · View at Scopus
  85. E. G. Nabel, “Cardiovascular disease,” The New England Journal of Medicine, vol. 349, no. 1, pp. 60–72, 2003. View at Publisher · View at Google Scholar · View at Scopus
  86. B. G. Nordestgaard and A. Varbo, “Triglycerides and cardiovascular disease,” The Lancet, vol. 384, no. 9943, pp. 626–635, 2014. View at Publisher · View at Google Scholar · View at Scopus
  87. J.-L. Chiasson and J. L. Lorier, “Glycaemic control, cardiovascular disease, and mortality in type 2 diabetes,” The Lancet, vol. 384, no. 9958, pp. 1906–1907, 2014. View at Publisher · View at Google Scholar · View at Scopus