Coronary Microvascular Smooth Muscle Cells Contribute to Heart Failure in Diabetes Mellitus by Increasing Methylglyoxal Flux

Prognosis for patients with type 1 diabetes mellitus (T1DM) who have heart failure is poor because of an incomplete understanding of molecular cues that trigger it and a lack of specific pharmacologic agents/strategies to slow/reverse its development. Supra-physiologic levels of the α-oxoaldehyde methylglyoxal (MG) have emerged as a possible cue. However, its source remains poorly characterized. Here we investigated MG levels and expression of its degrading and synthesizing enzymes glyoxalase-I (Glo-I) and vascular adhesion protein-1 (VAP-1) in ventricular tissues from rats with chronic streptozotocin-induced T1DM. We also used a gene transfer approach to prevent Glo-I downregulation in ventricular tissues to determine if it would be cardio-protective. When compared to controls, hearts of rats with chronic T1DM (10 -12 weeks) had 5-fold higher MG in ventricular tissues, 2.2-fold lower level of Glo-I in ventricular tissues and 2.5-fold higher in coronary microvascular smooth muscle cells (cSMCs). Preventing Glo-I levels downregulation in myocytes and cSMCs of rats by injecting them with an adeno-associated virus contain Glo-I driven by the endothelin promoter one week after the onset of T1DM, attenuated ventricular MG increase, with no effect in blood MG. Increasing Glo-I also blunted VAP-1 upregulation in cSMCs, attenuated microvascular leakage, inflammation, and fibrosis. These data support the notion that an increase in MG arising in part from increased expression of VAP-1 is contributing to HF development in T1DM rats and lowering ventricular MG levels T1DM rats is cardio-protective.