Abstract
Myocardial ischemia or hypoxia can induce myocardial fibroblast proliferation and myocardial fibrosis. Hydrogen sulfide (H2S) is a gasotransmitter with multiple physiological functions. In our present study, primary cardiac fibroblasts were incubated with H2S donor sodium hydrosulfide (NaHS, 50 μM) for 4 h followed by hypoxia stimulation (containing 5% CO2 and 1% O2) for 4 h. Then, the preventive effects on cardiac fibroblast proliferation and the possible mechanisms were investigated. Our results showed that NaHS reduced the cardiac fibroblast number, decreased the hydroxyproline content; inhibited the EdU positive ratio; and down-regulated the expressions of α-smooth muscle actin (α-SMA), the antigen identified by monoclonal antibody Ki67 (Ki67), proliferating cell nuclear antigen (PCNA), collagen I, and collagen III, suggesting that hypoxia-induced cardiac fibroblasts proliferation was suppressed by NaHS. NaHS improved the mitochondrial membrane potential and attenuated oxidative stress, and inhibited dynamin-related protein 1 (DRP1), but enhanced optic atrophy protein 1 (OPA1) expression. NaHS down-regulated receptor interacting protein kinase 1 (RIPK1) and RIPK3 expression, suggesting that necroptosis was alleviated. NaHS increased the sirtuin 3 (SIRT3) expressions in hypoxia-induced cardiac fibroblasts. Moreover, after SIRT3 siRNA transfection, the inhibitory effects on cardiac fibroblast proliferation, oxidative stress, and necroptosis were weakened. In summary, necroptosis inhibition by exogenous H2S alleviated hypoxia-induced cardiac fibroblast proliferation via SIRT3.
Highlights
Ischemic heart disease is a leading cause of death worldwide, which may lead to severe perioperative ischemia and infarction [1]
The assessment of the cardiac fibroblast number by cell counting Kit-8 (CCK-8) demonstrated that hypoxia significantly increased the optical density value of the cardiac fibroblasts, which was attenuated by NaHS (Figure 1B)
We found that the concentration of hydroxyproline in the culture medium of cardiac fibroblasts with hypoxia was higher than that with normoxia
Summary
Ischemic heart disease is a leading cause of death worldwide, which may lead to severe perioperative ischemia and infarction [1]. As the common pathophysiological characteristic of ischemic heart diseases, usually induces cellular oxidation and reduction unbalance, mitochondrial oxidative phosphorylation disorder, adenosine triphosphate (ATP) production impairment, and eventually myocardial infarction exacerbation [2]. The damaged tissue due to persistent hypoxia in myocardial infarction can be replaced by fibrous scar with fibroblasts and myofibroblasts. The reparative fibrosis is important to prevent ventricular wall rupture, excessive fibrous reaction and reactive fibrosis are prone to induce gradual damage of cardiac function, and lead to heart failure [3]. The prevention of excessive myocardial fibrosis caused by hypoxia is beneficial to cardiac function. There is still a lack of effective methods for hypoxia-induced myocardial fibrosis
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