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(a) ROS Generation by NADPH oxidases in heart and cardiovascular diseases. Nox2 activation and ROS production in the stimulation of pressure overload LV hypertrophy and Ang II-induced cardiac hypertrophy [5, 6, 8, 11]. Induction of atherosclerosis, hypertension, and myocardial remodeling by transforming growth factor-beta- (TGF-β-) stimulated NADPH oxidase-dependent ROS production [13]. Stimulation of mitochondrial dysfunction, apoptosis, LV dysfunction, cardiac dysfunction, and cardiac adaptation to chronic stress by Nox4-dependent superoxide generation [19–21]. Nox1-dependent extracellular superoxide in coronary arterial myocytes [22]. |
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| Nox2 → ROS → pressure overload LV hypertrophy | Li et al. [6] |
| Nox2 → ROS → Ang II-induced cardiac hypertrophy | Nakagami et al. [5] |
| Nox2 → activation in LV myocardium after MI | Doerries et al. [8] |
| Rac1-regulated Nox2 → Ang II-Akt activation → cardiomyocyte hypertrophy | Hingtgen et al. [11] |
| TGF-β→ NADPH oxidase → ROS → atherosclerosis↑, hypertension↑ → myocardial remodeling | Buday et al. [13] |
| Nox4 → ROS → mitochondrial dysfunction, apoptosis, LV dysfunction in response to pressure overload | Kuroda et al. [19] |
| Nox4 overexpression → O2 •−→ cardiac dysfunction → fibrosis, apoptosis | Ago et al. [20] |
| Nox4 → O2 •−→ cardiac adaptation to chronic stress | Zhang et al. [21] |
| Nox1 → extracellular O2•−↑ in coronary arterial myocytes | Zhang et al. [22] |
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(b) Xanthine oxidase as ROS producer in heart and cardiovascular diseases. Suppression of extracellular (ecSOD) and impaired endothelium-mediated vasodilation (FDD) in heart failure by Ang II-XO-produced superoxide [32, 33]. XO activation in dilated cardiomyopathy [34]. Impaired coronary NO bioavailability in patients with coronary artery disease (CAD) [35]. Expression of tumor necrosis factor (TNF-α), XO activation, and superoxide generation in myocardial I/R and coronary endothelial dysfunction [37]. Superoxide production by xanthine oxidoreductase and NADPH oxidase in hypertensive rats with diastolic heart failure [38]. Impairment of S-nitrosylation of the ryanodine receptor in spontaneously hypertensive heart failure rats by XO-generated superoxide [39]. |
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| AngII → XO → O2 •−→ ecSOD↓→ impaired FDD in heart failure | Landmesser et al. [32, 33] |
| Dilated cardiomyopathy → XO activity↑ | Duncan et al. [34] |
| XO → ROS → NO↓ in patients with CAD | Baldus et al. [35] |
| I/R → TNF-α→ XO activation → O2 •−→ coronary endothelial dysfunction | Zhang et al. [37] |
| XO + NADPH oxidase → O2 •−→ diastolic heart failure | Yamamoto et al. [38] |
| XO → O2 •−→ S-nitrosolation↓→ cardiomyopathy, hypertensive heart | Gonzalez et al. [39] |
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(c) Mitochondrial ROS production in heart and cardiovascular diseases. Complex I as ROS producer in the failing myocardium [41]. Enhancement of coronary endothelial dysfunction and decrease in coronary blood flow (CBF) in congestive heart failure (CHF) in dogs by mitochondrial superoxide [44]. Ventricular ROS production by NADPH oxidase and mitochondria in a rat model of the right-ventricular (RV) heart failure with pulmonary arterial hypertension (PAH) [45]. TNF-α-induced impairment of Complex I in the left ventricle (LV) in rats by mitochondrial superoxide [46]. Suppression of Complex II in postischemic myocardium in the rats with coronary ligation by superoxide [48]. |
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| Complex I → ROS → failing myocardium | Ide et al. [41] |
| Mitochondria (?)→ O2 •−→ coronary endothelial dysfunction↓ in CHF in dogs | Chen et al. [44] |
| Complex II + NADPH oxidase → ROS → PAH → RV heart failure | Redout et al. [45] |
| TNF-α→ mitochondrial O2 •−→ Complex I activity↓, LV damage | Mariappan et al. [46] |
| O2 •−→ Complex II activity↓ in postischemic myocardium | Chen et al. [48] |
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(d) ROS and RNS signaling in preconditioning. Activation of the epidermal growth factor (EGF) receptor, phosphatidylinositol 3-kinase (PI3-K), Akt, ERK (?), NOS, and ROS-dependent (mito)K(ATP) channels by acetylcholine and an opioid receptor [59]. Preconditioning effects of Ang II at cardiac I/R injury via mitochondrial ROS-initiated cascade of NADPH oxidase-JNK and p38 protein kinases [60]. Menadione-dependent superoxide initiation of ischemic preconditioning and reduction of myocardial infarction by potassium channels (mK(ATP)) and p38 MAPK [62]. Anoxic preconditioning through NO-cGMP-PKG-KATP cascade [64]. Activation of glucose transporter type 4 GLUT-4 translocation mediated by ROS-induced Akt/eNOS/Cav-3 enzymatic cascade [65]. Mechanism of ischemic preconditioning through NOS, guanylyl cyclase, PKG, and KATP channels with subsequent ROS generation and activation of phospholipase C, PKC, PI3-K, and ERK kinases [67]. |
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| Acetylcholine or opioid receptor → EGF receptor↑, PI3-K ↑, Akt↑, ERK?, NOS↑ → ROS-dependent opening of (mito)K(ATP)channels PRECONDITIONING | Philipp et al. [59] |
| AngII → ROS → NADPH oxidase → JNK → p38 → PRECONDITIONING | Kimura et al. [60] |
| Menadione → O2 •−→ mK(ATP) opening → p38 → PRECONDITIONING | Yue et al. [62] |
| NO → c-GMP → PKG → KATP → ANOXIC PRECONDITIONING | Van-Cuong et al. [64] |
| GLUT-4 → ROS → Akt → eNOS → caveolin-3 → ISCHEMIC PRECONDITIONING | Koneru et al. [65] |
| p-NOS → NO → guanylyl cyclase → cGMP → PKG → KATP → ROS → phospholipase C → PKC → PI3-K → ERK → ISCHEMIC PRECONDITIONING | |
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| (e) ROS signaling in damaging enzymatic cascades in the heart. Expression of angiogenic growth factor and angiogenesis in I/R myocardium stimulated by NADPH oxidase-induced ROS [69]. Endothelium-dependent vascular endothelial growth factor regulation of coronary vascular tone by ROS/NADPH oxidase/PI3-K/Akt/eNOS cascade [70]. Reduction of oxidative damage in the heart with myocardial infarction by inhibition of PKCδ or activation of PKCε [71]. Activation of NADPH oxidase and superoxide overproduction through p38 kinase and MAPKAPK-2 kinase in the heart failure [72]. Stimulation of ROS-dependent activation of p38 and JNKs kinases in the isolated perfused amphibian heart by hyperthermia [73]. ROS formation, myofibrillar protein oxidation, and p38 kinase activation in failing rabbit heart [74]. Improvement of congestive heart failure (CHF) through thioredoxin (Trx) upregulation, inhibition of NADPH oxidase and ASK-1/JNK/p38-mediated apoptosis by 17β-Estradiol (E2) treatment [75]. Inhibition by crocetin of ROS-dependent MAPK/(MEK/ERK1/2) pathway and stimulation of hypertrophy in cardiac myocytes and fibroblasts [76]. Activation of JNK and p38 kinases and the induction of p53 and PUMA (p53 upregulated modulator of apoptosis) stimulated by MCP-1-induced protein (MCPIP) [77]. Protection of cardiomyocytes by IKK-NF-κB signaling cascade due to a decrease in oxidative stress and JNK activation [78]. Recombinant TNF- (rTNF-) induced superoxide production in cardiomyocytes and cardiofibroblasts, concomitant with expression of matrix metalloproteinases MMPs [79]. ROS-induced expression of phosphodiesterase type 5 (PDE5) in cardiac myocytes and the development of congestive heart failure (CHF) [80]. ROS production by NADPH oxidase and the activation of CaMKII (calmodulin kinase II) after depolarizations (EADs) and cardiac arrhythmias [81]. |
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| NADPH oxidase → ROS → Akt → ERK1/2 → angiogenesis in I/R myocardium | Chen et al. [69] |
| NADPH oxidase → ROS → PI3-K → Akt → eNOS → VEGF regulation of coronary vascular tone | Feng et al. [70] |
 | Monti et al. [71] |
| Heart failure → P38↑ → MAPKAPK-2 → NADPH oxidase → O2 •− ↑ + NO↓ | Widder et al. [72] |
| Hyperthermia → ROS↑ → p38↑ and JNKs ↑ in heart | Gaitanaki et al. [73] |
| P38 → ROS → LV stimulation in failing rabbit heart | Heusch et al. [74] |
| E2 → Trx↑ → NADPH oxidase↓→ ASK-1/c-Jun/p38↓→ apoptosis↓→ CHF recovery | Satoh et al. [75] |
| Crocetin → ROS/MEK/ERK1/2 ↓→ cardiac hypertrophy↓ | Cai et al. [76] |
 | Younce and Kolattukudy [77] |
| IKK-NF-κB → ROS ↓→ JNK↓→ pressure overload↓ | Hikoso et al. [78] |
| rTNF → PI3K → O2 •− ↑ → MMP↑ | Awad et al. [79] |
| ROS → PDE5↑ → CHF stimulation | Lu et al. [80] |
| EAD, arrhythmias → Ang II → NADPH oxidase → ROS → CaMKII ↑ | Zhao et al. [81] |
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(f) ROS signaling in gene/enzymatic processes in heart. Suppression of age-dependent cardiac hypertrophy, apoptosis, cardiac dysfunction, and expression of senescence markers by Sirt1 upregulation in response to low/moderate oxidative stress. In contrast enhancement by a high level of Sirt1 of these damaging disorders [82]. Sirt3 suppression of cardiac hypertrophic response through Foxo-dependent MnSOD and catalase and the suppression of ERK and PI3K/Akt activation [83]. p66Shc participation in an α 1-adrenergtic receptor (α 1-AR) pathway together with PKCε and PKCδ and the induction of Akt-FOXO3a phosphorylation in cardiomyocytes [84]. FoxO1 and FoxO3 nuclear localization and target gene activation by oxidative stress in cardiomyocytes [85]. |
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 | Alcendor et al. [82] |
| Sirt3 → MnSOD↑, catalase ↑ → ROS ↓→ PI3K/Akt/ERK↓→ Cardiac hypertrophy↓ | Sundaresan et al. [83] |
| P66Shc → PKCε and PKCδ→ Akt-FOXO3a phosphorylation → hypertrophy↓ | Guo et al. [84] |
| AMPK → FOX1 + FOX3 → MnSOD↑ + catalase↑ → survival | Sengupta et al. [85] |
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