Mechanical stretch promotes matrix metalloproteinase-2 and prolyl-4-hydroxylase α1 production in human aortic smooth muscle cells via Akt-p38 MAPK-JNK signaling

Abstract

Hypertension can increase mechanical stretch on the vessel wall, an important stimulus that induces collagen remodeling. Prolyl-4-hydroxylaseα1 (P4Hα1) and matrix metalloproteinases (MMPs) are essential for collagen synthesis and degradation. However, the effect of mechanical strain and collagen synthesis remains largely unknown. This study aimed to identify the effect of stretch on MMPs and P4Hα1 and the involved signaling pathways. Human aortic smooth muscle cells (HASMCs) were stimulated with mechanical stretch (0, 10% and 18% strain), and production of P4Hα1 as well as production and gelatinolytic activity of MMP-2 was force-dependently increased. Mechanical stretch at 18% also increased the expression of type I and III collagen and the phosphorylation of Akt, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). MMP-2 production and activity enhanced by 18% stretch were inhibited by the PI3K/Akt inhibitor LY294002. Blockade of p38 MAPK or JNK inhibited the promoting effect of stretch on P4Hα1. The in vivo model of aortic banding showed increased protein levels of MMP-2, P4Hα1 and collagen I and III in the aorta. Thus, mechanical stretch increased MMP-2 and P4Hα1 expression in HASMCs via AKT-P38 MAPK-JNK signaling, thereby inducing vascular remodeling.

Keywords: Human aortic smooth muscle cells; Hypertension; Matrix metalloproteinases; Mechanical stretch; Prolyl-4-hydroxylase α1.