Decreased Endogenous Production of Hydrogen Sulfide Accelerates Atherosclerosis

Abstract

A therosclerosis is characterized with plaque formation in large and medium-sized blood vessels. The stiffened and narrowed blood vessels limit blood circulation and increase plaque thrombogenicity, which threatens the functionality of vital organs such as the heart and brain. [1][2][3] The development of atherosclerosis is a chronic pathological process. Vascular remodeling and inflammation, endothelial dysfunction, smooth muscle cell (SMC) proliferation and migration, and accumulation of cholesterol-rich lipoproteins in blood vessel walls are early events of atherogenesis, resulting in the recruitment of circulating monocytes, their adhesion to endothelium via adhesion molecules, and their differentiation into macrophages. 4 The subendothelial accumulation of cholesterol-laden macrophages is morphologically recognized as foam cells. In humans, these fatty streaks can progress to more advanced lesions characterized by a lipid-rich necrotic core and a fibrous cap consisting of SMCs and collagen.Lesion rupture can result from the decreased viability of SMCs that is necessary for collagen production and for the structural integrity of the fibrous cap following the release of matrix metalloproteinases from apoptotic macrophages. 4-8 Editorial see p 2472 Clinical Perspective on p 2534Hydrogen sulfide (H 2 S), a member of the gasotransmitter family, plays a number of important physiological roles within the body, including protection against cardiovascular disease.9-11 Cystathionine γ-lyase (CSE) endogenously produces H 2 S in the cardiovascular system, 12,13 and the deficiency of CSE in mice leads to decreased endogenous H 2 S level, age-dependent increase in blood pressure, impaired endothelium-dependent vasorelaxation, and accumulation of homocysteine in the blood.14 Administration of NaHS (a H 2 S donor) protects rat aortic SMCs from the cytotoxicity caused Background-Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H 2 S) in the cardiovascular system. The deficiency of CSE in mice leads to a decreased endogenous H 2 S level, an age-dependent increase in blood pressure, and impaired endothelium-dependent vasorelaxation. To date, there is no direct evidence for a causative role of altered metabolism of endogenous H 2 S in atherosclerosis development. Methods and Results-Six-week-old CSE gene knockout and wild-type mice were fed with either a control chow or atherogenic paigen-type diet for 12 weeks. Plasma lipid profile and homocysteine levels, blood pressure, oxidative stress, atherosclerotic lesion size in the aortic roots, cell proliferation, and adhesion molecule expression were then analyzed. CSE-knockout mice fed with atherogenic diet developed early fatty streak lesions in the aortic root, elevated plasma levels of cholesterol and low-density lipoprotein cholesterol, hyperhomocysteinemia, increased lesional oxidative stress and adhesion molecule expression, and enhanced aortic intimal proliferation. Treatment of CSE-knockout mice with NaHS, but not N-acetylcysteine or ezetimibe, inhibited the acceler...

Hydrogen Sulfide and Endothelial Dysfunction: Relationship with Nitric Oxide

“…These animals also showed increased total plasma cholesterol and LDL-cholesterol levels when compared to WT mice fed with the same atherogenic diet. NaHS supplementation to atherogenic diet-fed CSE-KO mice improved plasma lipid profile and decreased atherosclerotic lesions [28]. Collectively, these studies suggest that NO and H 2 S play similar roles in the prevention of atherosclerosis.…”

“…GYY4137 (a slow H 2 S releasing molecule) decreased the atherosclerotic plaque formation and partially restored the endothelium-dependent relaxation of apoE-KO mouse aorta [162]. The direct evidence for the role of endogenous H 2 S in atherosclerosis development was reported in 2013, demonstrating that CSE-KO mice fed with atherogenic paigen-type diet, but not WT mice, developed early fatty streak lesions in the aortic root, increased aortic intimal proliferation and aortic adhesion molecule expression, and enhanced oxidative stress [28]. These animals also showed increased total plasma cholesterol and LDL-cholesterol levels when compared to WT mice fed with the same atherogenic diet.…”

“…EC dysfunction, hypertension, VSMC proliferation and migration, dyslipidemia, oxidative stress, and recruitment of inflammatory cells are the important factors involved in the development of atherosclerotic lesions [28,149]. NO and H 2 S share several athero-protective actions, including blood vessel relaxation and regulation of vascular tone, EC regeneration, inhibition of leukocyte adhesion, inhibition of platelet clumping to make the blood thinner, and prevention of proliferation and migration of VSMCs [150][151][152][153].…”

“…At the same time, vascular ECs are induced to express increased amounts of adhesion molecules (P-selectin and E-selectin) and integrins (ICAM-1 and VCAM-1), which encourage leukocyte adhesion to the vessel wall and their subsequent translocaiton into the intimal layer. This process is favoured by the chemotactic activity of oxLDL and by the reduced bioavailability of NO [1], or H 2 S [28]. Once recruited into the nascent atheromatous lesion, monocytes-derived macrophages ingest oxLDL to become foam cells and to form fatty streaks within the artery wall [27].…”

“…H 2 S protects the luminal surface of blood vessel from oxidative stress caused by ischemia/reperfusion injury, as well as from development of atherosclerotic lesions, [28,122].…”