Antioxidant Effects of Hydrogen Sulfide on Left Ventricular Remodeling in Smoking Rats Are Mediated via PI3K/Akt-Dependent Activation of Nrf2

Abstract

There is growing evidence that oxidative stress plays critical roles in the pathogenesis of cardiac remodeling. In the present study, we established a rat model of passive smoking and investigated the antioxidant effects of hydrogen sulfide (H2S) on smoking-induced left ventricular remodeling. Cardiac structure and function were evaluated using 2-dimensional echocardiography. Myocardial fibrosis was detected by Masson's trichrome staining and immunohistochemistry. Oxidative stress was assessed by measuring malondialdehyde levels, superoxide dismutase and glutathione peroxidase activities, and reactive oxygen species generation in the myocardium. Neonatal rat cardiomyocytes transfected with specific siRNA and exposed to cigarette smoke condensate and H2S donor sodium hydrosulfide were used to confirm the involvement of Nrf2 and PI3K/Akt signaling in the antioxidant effects of H2S. Our results indicated that H2S could protect against left ventricular remodeling in smoking rats via attenuation of oxidative stress. Moreover, H2S was also found to increase the phosphorylation of Akt and GSK3β and decrease the nuclear expression of Fyn, which consequently leads to nuclear translocation of Nrf2 and elevated expression of HO-1 and NQO1. In conclusion, H2S may exert antioxidant effects on left ventricular remodeling in smoking rats via PI3K/Akt-dependent activation of Nrf2 signaling.

Emerging role of hydrogen sulfide-microRNA crosstalk in cardiovascular diseases

“…DATS inhibits apoptosis by preventing caspase-3 activation, blunting phosphorylation of JNK and c-JUN, and inhibiting nuclear translocation of NF-B (80). H 2 S mitigates upregulation of ROS and prevents cell death associated with several disease states including hyperglycemia, hyper-homocysteinemia, smoke exposure, and I/R injury (49,54,144,145,156,165).…”

“…NaHS (8 Mol·kg Ϫ1 ·day Ϫ1 ) increases Nrf2 levels in cardiomyocytes, resulting in decreased ROS levels in smokeexposed rats (165). Furthermore, Nrf2 activation by DATS (10 M) reduces ROS in high glucose-treated cardiomyocytes (143).…”

“…Furthermore, Nrf2 activation by DATS (10 M) reduces ROS in high glucose-treated cardiomyocytes (143). In both cases, Nrf2 activation is the result of increased PI3K/Akt signaling induced by H 2 S supplementation (143,165). H 2 S administration before myocardial ischemia increases the nuclear localization of Nrf2 and protects the ischemic heart from injury (21).…”

“…H 2 S not only downregulates autophagy but it also induces PI3K and GSK3␤. PI3K and GSK3␤ upregulate Nrf2 for cardioprotection (65,143,165). In an in vivo I/R model, NaHS (100 M) increased phosphorylated mTOR complex 2, resulting in inactivation of cell death initiator Bim (Bcl-2 interacting mediator of cell death) for cell survival (166).…”

PI3K/SGK1/GSK3β signaling pathway is involved in inhibition of autophagy in neonatal rat cardiomyocytes exposed to hypoxia/reoxygenation by hydrogen sulfide

“…So we speculated that PI3K/SGK1/GSK3β signaling pathway may also contribute to the cardioprotective effect. The mechanism of the protective effect of H 2 S is focused on PI3K/AKT pathway at present [21][22][23] . In the present study we wanted to determine whether H 2 S could regulate autophagy in cardiomyocytes exposed to HR and exert cardioprotection through PI3K/SGK1 /GSK3β signaling pathway.…”