Background: More than 25% of middle-aged people living with diabetes mellitus (DM) have myocardial dysfunction including early onset diastolic dysfunction (DD), harbingers for symptomatic heart failure and frequent hospitalizations. This DD which is more prevalent in females than in males is associated with increased systemic inflammation, coronary microvascular dysfunction, myocardial fibrosis/stiffness and ischemia. Here we show using the db/db mouse model of DM that the diverse pathobiologies associated with DD are originating from accumulation of the glycolysis by-product, methylglyoxal (MG) arising from inflammation-induced downregulation of the MG-degrading enzyme glyoxalase-1 (Glo1).
Methods/Results: At six month of age, female db/db mice developed degree I-II DD, with increases in E:e’ ratio, and isovolumetric relaxation time. Speckle tracking analyses also indicated increased global longitudinal and circumferential strains. Histopathological analyses of ex vivo hearts showed increased amounts of the inflammation-induced protein vascular adhesion protein-1 (VAP-1), reduced level of Glo1, increased MG and the MG-adduct, MG-H1, microvascular leakage, micro-ischemia and fibrosis. Time to decay of myocytes evoked Ca2+ transient was also increased. Administration of a single injection of an engineered adeno-associated virus that uses the promoter of an inflammation-induced protein, endothelin-1 (AAV2/9-Endo-Glo1) to express Glo1 in hearts of three months db/db mice, attenuate coronary microvascular leakage, ischemia, fibrosis and myocardial and myocyte dysfunction, establishing a cause-effect relationship between MG accumulation and myocardial dysfunction in db/db mice.
Conclusions: These new data implicates accumulation of MG as a contributing cause of myocardial dysfunction type 2 DM. They also show that an AAV driven by the promoter of an inflammation-induced protein to express Glo1 in hearts of db/db mice can successfully attenuate DD.
K. Bidasee: None.
