The Antioxidant Edaravone Attenuates Pressure Overload–Induced Left Ventricular Hypertrophy

Abstract

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.

Quantitative Phosphoproteomic Study of Pressure-Overloaded Mouse Heart Reveals Dynamin-Related Protein 1 as a Modulator of Cardiac Hypertrophy

“…Recently, DRP1 was shown to mediate the oxygeninduced ductus arteriosus smooth muscle cell (DASMC) contraction and proliferation by increasing cytosolic calcium and ROS (66). Because ROS and calcium are proposed intracellular secondary messengers for cardiac hypertrophy (67)(68)(69), TAB may lead to DRP1 activation, which increases intracellular ROS and calcium levels and thus induces cardiac hypertrophy. Another possible mechanism for the involvement of DRP1 in cardiac hypertrophy is the regulation of mitochondrial metabolism.…”

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

“…Decreased infarct size in superoxide dismutase (SOD)-producing transgenic mice suggests direct evidence for the role of involvement of ROS in MI. 22,23 In limited investigations, the use of antioxidants such as mercaptopropionyl glycine, edaravone and probucol have demonstrated varied effects on remodeling in animal models of MI, [24][25][26][27][28][29][30][31][32] with improvement in collagen content and histological changes. In this study, we sought to delineate the role of chronic tobacco smoke leading up to an acute MI by focusing on oxidative stress coupled with inflammation in the genesis of events leading to cardiac dysfunction and histological extent of damage.…”

Chronic sodium hydrosulfide treatment decreases medial thickening of intramyocardial coronary arterioles, interstitial fibrosis, and ROS production in spontaneously hypertensive rats

“…In recent years, accumulating evidence has suggested that H 2 S plays a pivotal role in cardiovascular regulation (27,16). Intravenous bolus injection of H 2 S [in the form of sodium hydrosulfide (NaHS), a water-soluble H 2 S donor] transiently decreased BP in rats by [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]7). H 2 S has been further shown to dilate rat aortic tissues by opening ATPsensitive potassium channels (K ATP channels) in vascular smooth muscle cells (VSMC) (31).…”