A role for angiotensin and oxidative stress in diabetes‐induced coronary artery remodeling

Abstract

Coronary artery (CA) remodeling may lead to increased arterial stiffness and decreased coronary flow reserve. The molecular mechanisms that dictate diabetes‐induced CA remodeling are undefined. This study established a link between oxidative stress, angiotensin II (Ang II), CA remodeling and stiffness in Type 2 diabetic mice. CA (<100 μ) were isolated from 16 wk heterozygous (Db/db) and diabetic (db/db) mice ± treatment with the NADPH‐oxidase inhibitor apocynin (5mM) or the AT1R blocker candesartan (1mg/kg/day). Mean arterial pressure, measured by telemetry, was similar between groups. CA were mounted on a pressure myograph for measurement of structural and passive mechanical properties. Significant inward remodeling was detected in db/db vs. Db/db, defined by increased wall thickness, media:lumen ratio, remodeling index and decreased compliance. This inward remodeling in db/db CA was associated with increased oxidative stress and collagen accumulation as measured by DHE and picrosirius red staining respectively. Immunoblot analysis indicted that basal JNK, ERK, and AKT phosphorylation were increased in db/db CA tissue lysates vs. Db/db. In vivo treatment with apocynin or candesartan reduced inward CA remodeling. These data suggest that increased oxidative stress and Ang II is critical for altered structural and functional remodeling of CA in Type 2 diabetes. Supported by HL056046 and P20RR18766 (PAL).