Transgenic mice with cardiac-directed C1C2, a fusion protein of the intracellular C1 and C2 segments of adenylyl cyclase type 6, had normal left ventricular (LV) function, but diminished cAMP generation. Cardiac myocytes from C1C2 mice showed increased Ca2+ release. Mice underwent continuous isoproterenol infusion to stress the heart. In C1C2 mice, sustained isoproterenol infusion increased rather than decreased LV function. LV SERCA2a and Ca2+ release were increased. Reduced cAMP generation and resistance to catecholamine cardiomyopathy are attractive features of this potential heart failure therapeutic.
Gao, M. H., Lai, N. C., Giamouridis, D., Kim, Y. C., Tan, Z., Guo, T., … Hammond, H. K. (2016). Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation. JACC: Basic to Translational Science. Elsevier Inc. https://doi.org/10.1016/j.jacbts.2016.08.004