The inhibition of calpains ameliorates vascular restenosis through MMP2/TGF-β1 pathway

Abstract

Restenosis limits the efficacy of vascular percutaneous intervention, in which vascular smooth muscle cell (VSMC) proliferation and activation of inflammation are two primary causal factors. Calpains influence VSMC proliferation and collagen synthesis. However, the roles of calpastatin and calpains in vascular restenosis remain unclear. Here, restenosis was induced by ligating the left carotid artery, and VSMCs were pretreated with platelet-derived growth factor (PDGF)-BB. Adenovirus vector carrying MMP2 sequence and specific small interfering RNA against calpain-1/2 were introduced. Finally, restenosis enhanced the expression of calpain-1/2, but reduced calpastatin content. In calpastatin transgenic mice, lumen narrowing was attenuated gradually and peaked on days 14–21. Cell proliferation and migration as well as collagen synthesis were inhibited in transgenic mice, and expression of calpain-1/2 and MMP2/transforming growth factor-β1 (TGF-β1). Consistently, in VSMCs pretreated with PDGF-BB, calpastatin induction and calpains inhibition suppressed the proliferation and migration of VSMCs and collagen synthesis, and reduced expression of calpain-1/2 and MMP2/TGF-β1. Moreover, simvastatin improved restenosis indicators by suppressing the HIF-1α/calpains/MMP2/TGF-β1 pathway. However, MMP2 supplementation eliminated the vascular protection of calpastatin induction and simvastatin. Collectively, calpains inhibition plays crucial roles in vascular restenosis by preventing neointimal hyperplasia at the early stage via suppression of the MMP2/TGF-β1 pathway.

TGF‐β‐mediated exosomal lnc‐MMP2‐2 regulates migration and invasion of lung cancer cells to the vasculature by promoting MMP2 expression

“…Previous studies reported roles for MMP2 in regulating lung cancer invasion and vascular permeability . In the present study, exogenous overexpression and interference experiments showed that lnc‐MMP2‐2 promoted lung cancer invasion and increased vascular permeability, and that lnc‐MMP2‐2 expression was markedly higher in lung cancer tissues than in normal controls.…”

Inhibition of Starvation-Triggered Endoplasmic Reticulum Stress, Autophagy, and Apoptosis in ARPE-19 Cells by Taurine through Modulating the Expression of Calpain-1 and Calpain-2

“…The main calpain isoforms in the brain are μ-calpain (calpain-1) and m-calpain (calpain-2) [ 24 ]. Some studies have indicated that, under certain conditions, calpain activation could cause tissue damage and cell death [ 25 , 26 ]. However, some studies showed that calpain-1 and calpain-2 play opposite roles in retinal ischemia/reperfusion injury but both, calpain-1 and calpain-2, provide neuroprotection in chronic myeloid leukemia [ 27 , 28 ].…”

Defective Protein Catabolism in Atherosclerotic Vascular Inflammation

“…Furthermore, osteopontin and osteonectin levels in VSMCs were reduced by the overexpression of calpain-1 in rats, inducing the calcification and fibrosis in the arteries of aged rats ( 67 ). Furthermore, VSMC proliferation and collagen synthesis were accelerated during ligation-induced carotid restenosis in mice, which was opposed by the transgenic overexpression of calpastatin ( 68 ). Therefore, calpain systems have a pivotal role in inflammation-related fibrogenic responses in VSMCs.…”