Hydrogen sulfide attenuates mitochondrial dysfunction-induced cellular senescence and apoptosis in alveolar epithelial cells by upregulating sirtuin 1.

Ruijuan Guan,Wei Liu,Mingjing Ding,Ziying Li,Wenju Lu,Jingyi Xu,Bingxian Deng,Zhou Cai,Jing Qian,Yuanyuan Li,Jingpei Li,Chun Tang,Hongwei Yao,Jian Wang,Dejun Sun

doi:10.18632/aging.102454

Abstract

Hydrogen sulfide (H2S), an endogenous gaseous signal molecule, regulates many pathologies related to aging. Sirtuin 1 (SIRT1) has been shown to protect against mitochondrial dysfunction and other pathological processes, including premature senescence. This study was aimed to investigate whether and how H2S attenuates senescence and apoptosis of alveolar epithelial cells via a SIRT1-dependent mechanism. Our results showed that treatment with sodium hydrosulfide (NaHS), a donor of H2S, attenuated cigarette smoke extract (CSE)-induced oxidative stress, mitochondrial dysfunction, cellular senescence and apoptosis in A549 cells. This was associated with SIRT1 upregulation. SIRT1 activation by a pharmacological activator, SRT1720, attenuated CSE-induced oxidative stress and mitochondrial dysfunction in A549 cells. While SIRT1 inhibition by EX 527 or silencing by siRNA transfection significantly attenuated or abolished the ability of NaHS to reverse the CSE-induced oxidative stress, mitochondrial dysfunction and the imbalance of mitochondrial fusion and fission. Also, SIRT1 inhibition or silencing abolished the protection of NaHS against CSE-induced cellular senescence and apoptosis. In conclusion, H2S attenuates CSE-induced cellular senescence and apoptosis by improving mitochondrial function and reducing oxidative stress in alveolar epithelial cells in a SIRT1-dependent manner. These findings provide novel mechanisms underlying the protection of H2S against cigarette smoke-induced COPD.

Highlights

Cigarette smoke (CS) is one of the most common inhaled irritants of the respiratory tract; it contains approximately 5000 chemical compositions including particles, gases, free radicals and reactive chemicals [1]
We demonstrated that cigarette smoke extract (CSE) induced oxidative stress, mitochondrial damage, senescence, and apoptosis in alveolar epithelial cells
We found that the protective effect of hydrogen sulfide (H2S) on these effects was associated with the upregulation of Sirtuin 1 (SIRT1)

Summary

Introduction

Cigarette smoke (CS) is one of the most common inhaled irritants of the respiratory tract; it contains approximately 5000 chemical compositions including particles, gases, free radicals and reactive chemicals [1]. Alveolar epithelial cells (AECs) appear to be a direct target for oxidant injury of the various cell types of the lung. Accelerated cellular senescence and apoptosis, as well as the accumulation of mitochondrial damage, in the alveolar epithelium by CS are www.aging-us.com considered as essential processes in the pathogenesis of smoking-associated pulmonary diseases, including COPD [4, 5]. The protection of AECs from injury by CS appears to be crucial for the management of numerous lung diseases associated with cigarette smoking. SIRT1 has been shown to regulate many physiological and pathophysiological processes, including cellular senescence/aging, apoptosis, stress resistance, metabolism and autoimmunity [9]. Pharmacological interventions that activate SIRT1 signaling in epithelial cells might be beneficial in the prevention and treatment of tissue damage associated with prolonged oxidative stress

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