Peroxisome Proliferator-Activated Receptor-γ Is Critical to Cardiac Fibrosis

Table 3

Effects of PPAR ligands on hypertension related cardiac fibrosis.

Study model	Dose/duration/route	Major cardiac findings and conclusions	Ref.
Male SHR and WKY rats, 8 weeks old; Cell culture: CFs form SD rats, 1-2 days old	Curcumin 100 mg/kg/d or curcumin 100 mg/kg/d plus GW9662 10 mg/kg/d for 12 weeks, gavage	Curcumin attenuates cardiac fibrosis in SHRs and inhibits Ang II- induced production of CTGF, PAI-1, ECM, TGFβ1, and phosphorylation of Smad2/3 in CFs in vitro	[10]
Male DnTGFβRII and WT C57BL/6 mice, 8–10 weeks old subjected to TAC	Rosiglitazone 10 mg/kg/d or T0070907 1.5 mg/kg/d for 3 weeks, gavage	Downregulation of endogenous PPAR expression by TGFβ may be involved in pressure overload-induced cardiac fibrosis	[42]
Male Wistar rats, weights 250–300 g subjected to abdominal aortic banding at 4 weeks after ligation; Cell culture: CFs form Wistar rats, 1–3 days old	Rosiglitazone 6 g/kg/d or GW9662 0.2 g/kg/d 2 h prior to rosiglitazone 6 g/kg/d for 1 week, intraperitoneal injection	Activation of PPAR significantly inhibited cardiac remodeling by suppression the expressions of Brq1 and TGF1 through the NF-κB pathway	[43]
Male SHRSP and WKY rats, 24 weeks old	Pioglitazone 10 mg/kg/d for 8 weeks, mixed with food	Pioglitazone decreased interstitial fibrosis and number of myofibroblasts; mRNA levels of collagen I and BNP; MMP2 activity and protein level of CTGF. However, the mRNA level of collagen III and TGFβ1, MMP9 activity, and ROS production were not improved	[44]
Male SHRSP, 6 weeks old	Pioglitazone 10 mg/kg/d for 20 weeks, mixed with food	Subepicardial interstitial fibrosis, left ventricular NF-κB and AP-1 binding activities, the TNFα expression, and the adhesion of PECAM were decreased by pioglitazone treatment	[45]
Male SHRSP and WKY rats, 11 weeks old	Pioglitazone 1 mg/kg/d or 2 mg/kg/d, candesartan 0.3 mg/kg/d for 4 weeks, gavage	Pioglitazone suppressed cardiac inflammation and fibrosis and reduced vascular endothelial dysfunction by inhibition of cardiovascular NADPH oxidase, and the combination of pioglitazone and candesartan exerted more beneficial effects	[46]
Male C57BL/6J rats, 8 weeks old subjected to abdominal aortic banding	Ciglitazone 2 mg/kg/d for 4 weeks, administered in drinking water	Ciglitazone decreased interstitial and perivascular fibrosis and inhibition of an induction of NOX4, iNOS, MMP-2/MMP-13 expression, and collagen synthesis/degradation	[47]
Male inbred Dahl salt- sensitive rats, 7 weeks old	Pioglitazone 2.5 mg/kg/d for 4 weeks, gavage	Pioglitazone treatment ameliorated LV hypertrophy and fibrosis and improved diastolic function by activating AMPK signaling and inhibiting Akt signaling.	[48]

DnTGFRII: dominant-negative mutation of the human TGF type II receptor, WT: wild type, TGF: transforming growth factor, TAC: transverse aortic constriction, CFs: cardiac fibroblasts, NF-κB: nuclear factor-κB, SHR: spontaneously hypertensive rats, WKY: Wistar Kyoto rats, SD: Sprague-Dawley, CTGF: connective tissue growth factor, PAI-1: Plasminogen activator inhibitor-1, ECM: extracellular matrix, SHRSP: stroke-prone spontaneously hypertensive rats, BNP: brain natriuretic peptide, MMP: matrix metalloproteinases, ROS: reactive oxygen species, NADPH: nicotinamide adenine dinucleotide phosphate, NOX4: nicotinamide adenine dinucleotide phosphate oxidase 4, iNOS: inductive nitric oxide synthase, AP-1: activator protein-1, TNF: tumor necrosis factor, PECAM: platelet endothelial cell adhesion molecule, and AMPK: adenosine monophosphate-activated protein kinas.