Smooth Muscle Cells Are the Source of Heart Failure‐Causing Methylglyoxal in Diabetes Mellitus

Abstract

Heart failure/diabetic cardiomyopathy (DC) is an established case of morbidity and mortality in individuals with diabetes mellitus (DM). Yet, its molecular triggers remain undefined. Supra‐physiologic levels of the dicarbonyl species methylglyoxal (MG) has emerged as a leading candidate since it triggers several of the pathobiologies reported in DC. Why/how MG increases in the heart in DM remains undefined. Here left ventricular tissues from DM patients (Type 1 and Type 2 DM) and Type 1 DM rats were used to assess protein levels of the MG synthesizing and degradation enzymes, vascular adhesion protein‐1 (VAP‐1) and glyoxalase‐I (Glo‐I), respectively. Type 1 DM rats were also used to determine if targeted increase of Glo‐I in the heart would be cardio‐protective. In left ventricular tissues from patients and rats with DM, VAP‐1 was upregulated in smooth muscle cells (SMCs) and Glo‐I was reduced in SMCs and ventricular myocytes. MG and its metabolite argpyrimidine were also upregulated in left ventricular tissues. Increasing Glo‐I protein in SMCs and myocytes of Type 1 DM rats using a custom‐designed adeno‐associated virus blunted myocyte dysregulation and DC progression. Glo‐I restoration also attenuated VAP‐1 upregulation, lowered MG production, prevented microvascular leakage, and reduced mitochondria ROS generation, NF‐κB activation and TNF‐α production. It also blunted argpyrimidine modification and dysregulation of the sarcoplasmic reticulum Ca2+ cycling proteins, RyR2 and SERCA2a. From these new data we conclude that the myocyte‐dysregulating and heart failure‐causing increase in MG during DM arises from increased expression of VAP‐1 in ventricular SMCs and from decreased expression of Glo‐I in SMCs and ventricular myocytes. They also suggest that lowering SMCs‐generated MG could also be a new therapeutic strategy to blunt heart failure/DC development in DM.Support or Funding InformationGTRP 1053, UNMC, UNeMED