Reactive Oxygen Species Mediate Alpha-adrenergic Receptor-stimulated Hypertrophy in Adult Rat Ventricular Myocytes

Amin, Jay; Xiao, Lei; Pimental, David R.; Pagano, Patrick J.; Singh, Krishna; Sawyer, Douglas B.; Colucci, Wilson S.

doi:10.1006/jmcc.2000.1285

Cited by 161 publications

(115 citation statements)

References 38 publications

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“…An in vitro study suggested that the stimulation of ␤-adrenergic receptors located on cardiomyocytes induces hypertrophy, which is not mediated by increased ROS production. 13 In the present work, the NAD(P)H oxidase selective inhibitor, apocynin, prevented the ISOinduced cardiac hypertrophy, suggesting that NAD(P)H oxidase-dependent oxidative stress is involved in this in vivo model. ␤-Adrenergic receptor stimulation is likely involved, because the nonselective ␤-blocker propranolol had a similar effect to apocynin.…”

Section: -Ht 2b R Blockade Prevents O 2 ؊ -Mediated Iso-induced Carsupporting

confidence: 59%

Serotonin 5-HT _2B Receptor Blockade Prevents Reactive Oxygen Species–Induced Cardiac Hypertrophy in Mice

et al. 2008

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Abstract-We established previously that 5-HT 2B receptors are involved in cardiac hypertrophy through the regulation of hypertrophic cytokines in cardiac fibroblasts. Moreover, the generation of reactive oxygen species and tumor necrosis factor-␣ through the activation of reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase has been implicated in cardiac hypertrophy. In this study, we investigated whether 5-HT 2B receptors could be involved in the development of cardiac hypertrophy associated with superoxide anion production. Therefore, we measured the effects of serotonergic 5-HT 2B receptor blockade on left-ventricular superoxide anion generation in 2 established pharmacological models of cardiac hypertrophy, ie, angiotensin II and isoproterenol infusions in mice. Angiotensin II infusion for 14 days increased superoxide anion concentration (ϩ32%), NAD(P)H oxidase maximal activity (ϩ84%), and p47 phox NAD(P)H oxidase subunit expression in the left ventricle together with hypertension (ϩ37 mm Hg) and cardiac hypertrophy (ϩ17% for heart weight:body weight). The 5-HT 2B receptor blockade by a selective antagonist (SB215505) prevented the increase in cardiac superoxide generation and hypertrophy. Similarly, infusion for 5 days of isoproterenol increased left-ventricular NAD(P)H oxidase activity (ϩ48%) and cardiac hypertrophy (ϩ31%) that were prevented by the 5-HT 2B receptor blockade. Finally, in the primary culture of left-ventricular cardiac fibroblasts, angiotensin II and isoproterenol stimulated NAD(P)H oxidase activity. This activation was prevented by SB215505. These findings suggest that the 5-HT 2B receptor may represent a new target to reduce cardiac hypertrophy and oxidative stress. Its blockade affects both angiotensin II and ␤-adrenergic trophic responses without significant hemodynamic alteration. Key Words: 5-HT 2B Ⅲ NAD(P)H oxidase Ⅲ superoxide anion Ⅲ angiotensin Ⅲ adrenergic Ⅲ cardiac Ⅲ hypertrophy P athological left ventricular hypertrophy has been associated with increased production of reactive oxygen species (ROS). Recent works have shown that antioxidants inhibit in vitro cardiomyocyte hypertrophy and in vivo aortic bandinginduced left ventricular hypertrophy. 1 The cardiac ROS production can be triggered by factors such as angiotensin II (Ang II), catecholamines, endothelin-1, tumor necrosis factor-␣ (TNF-␣), and serotonin but also by mechanical stretch. Among these factors, those that signal through the G q /PLC pathway seem to play a crucial role in the initiation and maintenance of cardiac hypertrophy and are known to stimulate the cardiac ROS generation through the phagocytetype reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase. 2 The gp91 phox -containing NAD(P)H oxidase plays a pivotal role in the response to Ang II via a pathway involving protein kinase C, c-Src, and phosphatidylinositol 3-kinase. 3 NAD(P)H oxidase reduces oxygen O 2 , leading to the formation of superoxide anion (O 2 ⅐Ϫ ), which can be either dismutated spontaneously to hydrogen pe...

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Section: -Ht 2b R Blockade Prevents O 2 ؊ -Mediated Iso-induced Carsupporting

confidence: 59%

Serotonin 5-HT _2B Receptor Blockade Prevents Reactive Oxygen Species–Induced Cardiac Hypertrophy in Mice

et al. 2008

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“…7 Furthermore, a number of neurohormonal and mechanical stressors that are associated with the heart failure phenotype augment ROS generation. 8,9 Prolonged exposure to ROS, in turn, results in cardiomyocyte dysfunction. 10 At a cellular level, elevated levels of ROS impair cardiomyocyte function by damaging ion channels as well as inhibiting contractility.…”

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confidence: 99%

Xanthine Oxidase Inhibition and Heart Failure

Hajjar

Leopold

2006

Circulation Research

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M yocardial dysfunction and heart failure perturb cardiovascular homeostatic signaling pathways as well as initiate a program of molecular, biochemical, and structural modifications to remodel the failing ventricle. Accumulating evidence suggests that the cardiovascular redox state plays an integral role in these processes. In fact, in the failing heart, elevated levels of reactive oxygen species (ROS) and cardiomyocyte oxidant stress are associated with maladaptive ventricular remodeling and a progressive decline in cardiovascular function.The association between ROS and heart failure has been established. Increased indices of oxidant stress have been measured in patients with congestive heart failure. In clinical studies, patients with heart failure were found to have evidence of lipid peroxidation and elevated 8-iso-prostaglandin F 2␣ levels 1-4 whereas in experimental models of heart failure, investigators have been able to directly measure increased ROS production from cardiomyocytes. 5,6 These findings have been corroborated in studies that measured ROS levels in explanted human hearts at the time of transplant. 7 Furthermore, a number of neurohormonal and mechanical stressors that are associated with the heart failure phenotype augment ROS generation. 8,9 Prolonged exposure to ROS, in turn, results in cardiomyocyte dysfunction. 10 At a cellular level, elevated levels of ROS impair cardiomyocyte function by damaging ion channels as well as inhibiting contractility. ROS disrupt the structural integrity of ion channels via membrane lipid peroxidation. 2,11 ROS also decrease expression and activity of the sarcoplasmic reticulum Ca 2ϩ ATPase SERCA2, 12 which is critical for effective cardiac calcium handling. Interestingly, ROS have also been shown to decrease myofilament calcium sensitivity by activation of ASK-1, a redox-sensitive kinase. ASK-1 phosphorylates troponin T and thereby decreases contractility and regulates calcium handling. 13 Concomitant with these adverse effects on cardiomyocyte function, ROS stimulates a number of responses associated with the ventricular remodeling processes. These include ROS-mediated activation of matrix metalloproteinases to alter the architecture of the extracellular matrix, 14 modulation of signal transduction pathways that initiate cardiomyocyte hypertrophy, 15 and apoptosis or cell death. 16 Taken together, these observations suggest that one mechanism to halt deleterious ventricular remodeling and abnormal cardiomyocyte functional responses is to decrease oxidant stress by limiting ROS production. ROS are derived from the superoxide anion, a one-electron reduction product of oxygen. In the myocardium, superoxide anion may be generated by both metabolic and enzymatic sources including mitochondrial respiration, xanthine oxidase (XO), NAD(P)H oxidases, and, when substrate or cofactors are not replete, uncoupled nitric oxide synthase(s). 17,18 In the failing heart, activation of these ROS-generating systems leads to the accumulation of superoxide anions and the formati...

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“…2 In cardiomyocytes, ROS have been found to be involved in cardiac hypertrophy in vitro 3 and to mediate the hypertrophy induced by several stimuli, such as mechanical stretch, 4,5 ␣ 1 -adrenergic receptor stimulation, 6,7 endothelin-1, 8 phenylephrine, 8 angiotensin II, 9 and tumor necrosis factor-␣ (TNF-␣). 9,10 Similar results have been obtained with in vivo study.…”

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confidence: 99%

The Antioxidant Edaravone Attenuates Pressure Overload–Induced Left Ventricular Hypertrophy

Tsujimoto

Hikoso²,

Yamaguchi³

et al. 2005

Hypertension

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Abstract-The free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) is used to treat patients with ischemic brain damage. We and others reported previously that in vitro and in vivo reactive oxygen species (ROS) act as second messengers to develop cardiac hypertrophy. In this study, we used an in vivo murine model of pressure overload-induced cardiac hypertrophy to examine the effects of edaravone on left ventricular hypertrophy. The animals were subjected to the transverse thoracic aorta constriction, and edaravone (10 mg/kg) was infused intraperitoneally twice daily. Seven days after the operation, we observed a significant increase in ROS production in hearts, which was eliminated by the treatment with edaravone. Pressure-overloaded hearts showed a significant increase in left ventricular weight/body weight ratio and the expression level of atrial natriuretic factor mRNA, which were attenuated by edaravone. It also reduced perivascular and intermuscular fibrosis and inhibited pressure overload-induced activation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream kinases of c-Jun N-terminal protein kinase and p38 mitogen-activated protein kinase. Edaravone attenuated the hypertrophic response even when the treatment was started after the onset of cardiac hypertrophic response. These findings indicate that edaravone significantly attenuates pressure overload-induced cardiac hypertrophy mediated through its antioxidative function and subsequent inhibition of ASK1 signaling pathway.

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Reactive Oxygen Species Mediate Alpha-adrenergic Receptor-stimulated Hypertrophy in Adult Rat Ventricular Myocytes

Cited by 161 publications

References 38 publications

Serotonin 5-HT _2B Receptor Blockade Prevents Reactive Oxygen Species–Induced Cardiac Hypertrophy in Mice

Serotonin 5-HT _2B Receptor Blockade Prevents Reactive Oxygen Species–Induced Cardiac Hypertrophy in Mice

Xanthine Oxidase Inhibition and Heart Failure

The Antioxidant Edaravone Attenuates Pressure Overload–Induced Left Ventricular Hypertrophy

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Reactive Oxygen Species Mediate Alpha-adrenergic Receptor-stimulated Hypertrophy in Adult Rat Ventricular Myocytes

Cited by 161 publications

References 38 publications

Serotonin 5-HT 2B Receptor Blockade Prevents Reactive Oxygen Species–Induced Cardiac Hypertrophy in Mice

Serotonin 5-HT 2B Receptor Blockade Prevents Reactive Oxygen Species–Induced Cardiac Hypertrophy in Mice

Xanthine Oxidase Inhibition and Heart Failure

The Antioxidant Edaravone Attenuates Pressure Overload–Induced Left Ventricular Hypertrophy

Contact Info

Product

Resources

About

Serotonin 5-HT _2B Receptor Blockade Prevents Reactive Oxygen Species–Induced Cardiac Hypertrophy in Mice

Serotonin 5-HT _2B Receptor Blockade Prevents Reactive Oxygen Species–Induced Cardiac Hypertrophy in Mice