P712Non-neuronal cholinergic system prevents coronary vascular dysfunction in diabetic heart
Abstract Background Diabetic individuals suffer extensive myocardial damage during ischemia due to impaired ATP production and coronary vascular dysfunction. The cardiomyocytes possess a non-neuronal cholinergic system (NNCS) as it has choline acetyltransferase (ChAT) to synthesize acetylcholine (ACh). ACh released from cardiomyocytes activates hypoxia-inducible factor-1 pathway in an auto/paracrine manner under non-hypoxic condition. Activation of this pathway via NNCS promotes angiogenesis and is a promising mechanism to target ischemia in diabetes. Aim To investigate if activation of NNCS could improve the coronary vasculature in diabetic heart. Methods Type-2 diabetic db/db mice with ventricle-specific ChAT transgene (db/db-ChAT-tg) and control db/db mice of 12- and 24-weeks old were used. Catheterization of the jugular vein and carotid artery was performed in combination with synchrotron radiation microangiography to visualize the in-vivo coronary circulation. Changes of the coronary circulation to ACh (10μg/kg/min) and sodium nitroprusside (SNP, 10μg/kg/min) were assessed. Immunofluorescence analysis was performed to measure the density of arterioles and capillaries ex-vivo. Results In comparison to db/db mice, the number of second and third order vessels was higher in the db/db-ChAT-tg mice of 12- and 24-weeks old under baseline condition. In response to ACh and SNP, number of third order vessels were further increased in the db/db-ChAT-tg mice of both ages. However, the magnitude of the diameter changes in db/db-ChAT-tg mice was comparable to that in db/db mice of both ages. Besides, the db/db-ChAT-tg mice had increased density of arterioles and capillaries compared to the db/db mice of both ages. Conclusion NNCS-induced angiogenesis prevents coronary vascular dysfunction in diabetic heart.