Mechanical stretching stimulates collagen synthesis via down-regulating SO2/AAT1 pathway

Abstract

The aim of the study was to investigate the role of endogenous sulfur dioxide (SO2)/ aspartate aminotransferase 1 (AAT1) pathway in stretch-induced excessive collagen expression and its mechanism. The mechanical stretch downregulated SO2/AAT1 pathway and increased collagen I and III protein expression. Importantly, AAT1 overexpression blocked the increase in collagen I and III expression, transforming growth factor-β1 (TGF- β1) expression and phosphorylation of Smad2/3 induced by stretch, but AAT1 knockdown mimicked the increase in collagen I and III expression, TGF- β1 expression and phosphorylation of Smad2/3 induced by stretch. Mechanistically, SB431542, a TGF-β1/Smad2/3 inhibitor, eliminated excessive collagen I and III accumulation induced by AAT1 knockdown, stretch or stretch plus AAT1 knockdown. In a rat model of high pulmonary blood flow-induced pulmonary vascular collagen accumulation, AAT1 expression and SO2 content in lung tissues of rat were reduced in shunt rats with high pulmonary blood flow. Supplement of SO2 derivatives inhibited activation of TGF- β1/Smad2/3 pathway and alleviated the excessive collagen accumulation in lung tissues of shunt rats. The results suggested that deficiency of endogenous SO2/AAT1 pathway mediated mechanical stretch-stimulated abnormal collagen accumulation via TGF-β1/Smad2/3 pathway.

Sulfur Dioxide Protects Against Collagen Accumulation in Pulmonary Artery in Association With Downregulation of the Transforming Growth Factor β1/Smad Pathway in Pulmonary Hypertensive Rats

“…8,27,28 Our previous studies found that SO 2 could alleviate abnormal collagen accumulation in small pulmonary arteries of hypoxic pulmonary hypertensive rats and in a mechanical stretch- stimulated cell model. 29,30 In our previous research, 11 the pulmonary vascular structural remodeling induced by monocrotaline was confirmed by an increase in the relative medial thickness and area of pulmonary arteries. With inhibition of endogenous SO 2 production by HDX, pulmonary arterial remodeling became worse in the monocrotaline plus HDX group than in the monocrotaline group, indicating that inhibition of endogenous SO 2 could aggravate pulmonary vascular remodeling in monocrotaline-treated rats.…”

“…SO 2 exerts important effects on the cardiovascular system, such as vasorelaxant and negative inotropic effects . Our previous studies found that SO 2 could alleviate abnormal collagen accumulation in small pulmonary arteries of hypoxic pulmonary hypertensive rats and in a mechanical stretch‐stimulated cell model . In our previous research, the pulmonary vascular structural remodeling induced by monocrotaline was confirmed by an increase in the relative medial thickness and area of pulmonary arteries.…”

Mechanical Strain Induces Distinct Human Scleral Fibroblast Lineages: Differential Roles in Cell Proliferation, Apoptosis, Migration, and Differentiation

“…Mechanical strain is a known inducer of ECM remodeling in a number of tissues and organs, such as skin, 15 lung tissue, 11,16 bone, 17 and vascular systems. 18 Alterations include cell reorientation, matrix composition, collagen, and elastin realignment.…”

Role of Endogenous Sulfur Dioxide in Regulating Vascular Structural Remodeling in Hypertension

“…The administration of SO 2 derivatives (0.54 mmol/kg: 0.18 mmol/kg, for eight weeks) could significantly reduce the mean pulmonary artery pressure and improve the pulmonary vascular pathological changes of the rats, as demonstrated by the decreased percentage of muscularized pulmonary arteries. Furthermore, Liu et al [ 46 ] found that SO 2 alleviated the protein expression of collagen I and collagen III.…”