Exogenous H2S modulates mitochondrial fusion–fission to inhibit vascular smooth muscle cell proliferation in a hyperglycemic state

Abstract

AimVascular smooth muscle cell (VSMC) proliferation in response to hyperglycemia is an important process in the development of arterial vessel hyperplasia. The shape change of mitochondria is dynamic and closely related to fission and fusion. Hydrogen sulfide (H2S) was confirmed to have anti-oxidative, anti-inflammatory and anti-proliferative effects. However, little it is known about its effects on mitochondrial morphology induced by hyperglycemia. The aim of the study is to demonstrate that H2S inhibits VSMC proliferation through regulating mitochondrial fission.Methods and resultsWe observe lower H2S levels as well as higher proliferative protein expression levels for proliferative cell nuclear antigen (PCNA) and cyclin D1 and higher mitochondrial fusion–fission protein expression levels for dynamin-related protein 1 (Drp 1) in human kidney arteries and in db/db mouse aorta. Exogenous H2S (100 μM NaHS) inhibits vascular smooth muscle cells of human pulmonary aorta(HPASMC) proliferation and migration in response to high glucose using the BrdU and scratch wound repair assays, decreases proliferative protein (PCNA and cyclin D1) expression, and reduces ROS production in the cytoplasm and mitochondria. When HPASMCs proliferate with a high glucose treatment, the mitochondria become small spheres with a short rod-shaped structure, whereas NaHS, a mitochondrial division inhibitor and siDrp prevent VSMC proliferation and maintain mitochondria as stationary and randomly dispersed with fixed structures.ConclusionExogenous H2S aids in inhibiting mitochondrial fragmentation and affects proliferation in db/db mice and HPASMCs by decreasing Drp 1 expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-016-0102-x) contains supplementary material, which is available to authorized users.

Endothelin-1 Downregulates Sulfur Dioxide/Aspartate Aminotransferase Pathway via Reactive Oxygen Species to Promote the Proliferation and Migration of Vascular Smooth Muscle Cells

“…A previous study showed that H 2 S acting as a gasotransmitter can inhibit the proliferation of vascular smooth muscle cells [38][39][40]. Some research reported that SO 2 could inhibit the proliferation and migration of myocardial fibroblasts [41].…”

Beyond a Gasotransmitter: Hydrogen Sulfide and Polysulfide in Cardiovascular Health and Immune Response

“…In this process, VSMCs make a transition from the contractile phenotype to a synthetic phenotype that allows vigorous cell proliferation and migration. Multiple studies have reported that NaHS inhibits VSMC proliferation and migration under the stimulation of serum, high levels of glucose, or homocysteine (43,160,177,205). Meanwhile, the apoptotic pathway is also activated in NaHS-treated VSMCs (190,191).…”

Pulmonary vascular dysfunction in metabolic syndrome

“…In an ex vivo study, high‐glucose treatment enhanced cell proliferation in human pulmonary arterial SMCs via increasing ROS generation (Sun et al . ), implying that pulmonary vascular resistance might be increased in diabetes. This will be discussed further in the ‘Hyperglycaemia and pulmonary hypertension’ section.…”