Abstract

Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with diabetes. Hcy decreases beta2‐AR response by (i) inhibiting Gs (stimulatory) adenylyl cyclase ‐dependent protein kinase signaling and (ii) directly competing with beta2‐AR for binding. Attenuation of beta2‐AR response causes down regulation of AKT (anti‐stress factor) and induction of matrix metalloproteinase‐9 (MMP‐9) that leads to contractile dysfunction. To test the hypothesis that during diabetes the intolerance to exercise is, in part, due to attenuation of beta2‐AR and Gs by HHcy that down regulates AKT and induces MMP‐9 leading to contractile dysfunction, C57BL/6J and beta‐ AR++/++ transgenic mice with and without high fat diet and db/db mice were put on swimming exercise. We demonstrated that beta2‐AR is down regulated, whereas MMP‐9 and Hcy are up regulated in the diabetic heart. Additionally, beta2‐AR antagonist impairs contractile function of cardiomyocytes, while the beta‐AR agonist improves it. Interestingly, exercise induces beta2‐AR response and improves contractile function of cardiomyocytes in db/db mice. The stimulation of beta2‐AR along with exercise has synergistic effect on improvement in contractile function in diabetes. These results suggest attenuation of sympathetic tone in diabetes and therapeutic potential of beta2‐AR agonist and exercise for diabetic cardiomyopathy.