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PDE 5 Inhibitor Tadalafil and Hydroxychloroquine Co-Treatment Provides Synergistic Protection against Type 2 Diabetes and Myocardial Infarction in Mice

This article has not been copyedited and formatted. The final version may differ from this version. Abstract Diabetes is associated with high risk of ischemic heart disease. We previously showed that phosphodiesterase 5 inhibitor-tadalafil (TAD) induces cardioprotection against ischemia/ reperfusion (I/R) injury in diabetic mice. Hydroxychloroquine (HCQ) is a widely used antimalarial and anti-inflammatory drug, which was reported to reduce hyperglycemia in diabetic patients. Therefore we hypothesized that combination of TAD and HCQ may induce synergistic cardioprotection in diabetes. We also investigated the role of insulin-Akt-mTOR signaling, which regulates protein synthesis and cell survival. Adult male db/db mice were randomized to receive vehicle, TAD (6 mg/kg), HCQ (50 mg/kg), or TAD+HCQ daily by gastric gavage for 7 days. Hearts were isolated and subjected to 30-min global ischemia followed by 1-hour reperfusion in Langendorff mode. Cardiac function and myocardial infarct size were determined. Plasma glucose, insulin and lipid levels and relevant pancreatic and cardiac protein markers were measured. Treatment with TAD+HCQ reduced myocardial infarct size (17.4±4.3% vs. 37.8±4.9% in Control group, P<0.05) and enhanced production of ATP. The TAD+HCQ combination treatment also reduced fasting blood glucose, plasma free fatty acids, and triglyceride levels. Furthermore, TAD+HCQ increased plasma insulin levels (513±73 vs. 232±30 mU/L, P<0.05), with improved insulin sensitivity, larger pancreatic β-cell area and pancreas mass. IGF-1 levels were also elevated by TAD+HCQ (343±14 vs. 262±22 ng/mL, P<0.05). The increased insulin/IGF-1 resulted in activation of downstream Akt/mTOR cellular survival pathway. These results suggest that combination treatment with TAD and HCQ could be a novel and readily translational pharmacotherapy for reducing cardiovascular risk factors and protecting against myocardial I/R injury in type 2 diabetes.