Abstract
Background and Purpose: Hydrogen (H2) has been shown to have a strong antioxidant effect on preventing oxidative stress-related diseases. The goal of the present study is to determine the pharmacodynamics of H2 in a model of isoproterenol (ISO)-induced cardiac hypertrophy.Methods: Mice (C57BL/6J; 8–10 weeks of age) were randomly assigned to four groups: Control group (n = 10), ISO group (n = 12), ISO plus H2 group (n = 12), and H2 group (n = 12). Mice received H2 (1 ml/100g/day, intraperitoneal injection) for 7 days before ISO (0.5 mg/100g/day, subcutaneous injection) infusion, and then received ISO with or without H2 for another 7 days. Then, cardiac function was evaluated by echocardiography. Cardiac hypertrophy was reflected by heart weight/body weight, gross morphology of hearts, and heart sections stained with hematoxylin and eosin, and relative atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) mRNA levels. Cardiac reactive oxygen species (ROS), 3-nitrotyrosine and p67 (phox) levels were analyzed by dihydroethidium staining, immunohistochemistry and Western blotting, respectively. For in vitro study, H9c2 cardiomyocytes were pretreated with H2-rich medium for 30 min, and then treated with ISO (10 μM) for the indicated time. The medium and ISO were re-changed every 24 h. Cardiomyocyte surface areas, relative ANP and BNP mRNA levels, the expression of 3-nitrotyrosine, and the dissipation of mitochondrial membrane potential (MMP) were examined. Moreover, the expression of extracellular signal-regulated kinase1/2 (ERK1/2), p-ERK1/2, p38, p-p38, c-Jun NH2-terminal kinase (JNK), and p-JNK were measured by Western blotting both in vivo and in vitro.Results: Intraperitoneal injection of H2 prevented cardiac hypertrophy and improved cardiac function in ISO-infused mice. H2-rich medium blocked ISO-mediated cardiomyocytes hypertrophy in vitro. H2 blocked the excessive expression of NADPH oxidase and the accumulation of ROS, attenuated the decrease of MMP, and inhibited ROS-sensitive ERK1/2, p38, and JNK signaling pathways.Conclusion: H2 inhibits ISO-induced cardiac/cardiomyocytes hypertrophy both in vivo and in vitro, and improves the impaired left ventricular function. H2 exerts its protective effects partially through blocking ROS-sensitive ERK1/2, p38, and JNK signaling pathways.
Highlights
Heart failure is a global pandemic affecting an estimated 26 million people worldwide, posing an enormous burden to both individuals and society (Ambrosy et al, 2014)
Increasing evidence suggests that diverse pathophysiological stimuli, including neurohumoral activation [such as angiotensin II (ANG II) and β-adrenoceptor stimulation], hypertension, ischemic heart diseases, myocarditis, and diabetic cardiomyopathy, will contribute to cardiac hypertrophy and heart failure partially via inducing the production of excessive reactive oxygen species (ROS; Li et al, 2002; Zhang et al, 2007b; Zhang et al, 2015)
We recently revealed that intraperitoneal injection of H2 protects against vascular hypertrophy induced by abdominal aortic coarctation (AAC) in vivo, and H2-rich medium attenuates proliferation and migration of vascular smooth muscle cells (VSMCs) stimulated by ANG II in vitro (Zhang et al, 2016)
Summary
Heart failure is a global pandemic affecting an estimated 26 million people worldwide, posing an enormous burden to both individuals and society (Ambrosy et al, 2014). ROS generated by NADPH oxidase was shown to stimulate and amplify mitochondrial ROS production and induce mitochondrial dysfunction, which can be reflected by the depression of mitochondrial membrane potential (MMP; Zorov et al, 2000; Dai et al, 2011a). Blocking ROS will improve mitochondrial function and block downstream hypertrophic signaling, preventing the development of cardiac hypertrophy and progression to heart failure. Consistent with this notion, recent studies revealed that strategies targeted ROS and downstream signaling pathways modulated by ROS could be a better approach to improve cardiac hypertrophy (Burgoyne et al, 2012). The goal of the present study is to determine the pharmacodynamics of H2 in a model of isoproterenol (ISO)-induced cardiac hypertrophy
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