Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation.
Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain Reverses Cardiac Dysfunction Caused by Sustained Beta-Adrenergic Receptor Stimulation.
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DOI：
10.1016/j.jacbts.2016.08.004
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Hammond HK
中科院分区：
文献类型：
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作者：
Gao MH;Lai NC;Giamouridis D;Kim YC;Tan Z;Guo T;Dillmann WH;Suarez J;Hammond HK
C1C2的心脏靶向表达减少cAMP的产生，但小鼠通过增加Ca2+处理维持正常的心功能。持续异丙肾上腺素输注降低正常小鼠的心脏功能，但改善心脏C1C2表达增加的小鼠的心脏功能。减少心脏cAMP生成和抵抗儿茶酚胺心肌病是这种潜在的心力衰竭治疗的吸引人的特点。去除AC6的大跨膜结构域并融合两个细胞内结构域提供了一个小分子C1C2，它复制了AC6的许多有益作用，但足够小，可以在AAV载体中表达用于基因转移。C1C2是细胞内腺苷酸环化酶6型C1和C2段的融合蛋白，具有心脏定向C1C2的转基因小鼠左心室功能正常，但cAMP的产生减少。C1C2小鼠心肌细胞显示Ca2+释放增加。小鼠连续输注异丙肾上腺素以刺激心脏。在C1C2小鼠中，持续输注异丙肾上腺素增加而不是降低左室功能。左室SERCA2a和Ca2+释放增加。减少cAMP生成和抵抗儿茶酚胺心肌病是这种潜在的心力衰竭治疗的吸引人的特点。
Cardiac-targeted expression of C1C2 reduces cAMP production yet mice maintain normal cardiac function through increased Ca2+ handling. Sustained isoproterenol infusion reduces heart function in normal mice, but improves heart function in mice with increased cardiac C1C2 expression. Reduced cardiac cAMP generation and resistance to catecholamine cardiomyopathy are attractive features of this potential heart failure therapeutic. Removing the large transmembrane domains of AC6 and fusing the two intracellular domains provides a small molecule, C1C2, that replicates many of the beneficial effects of AC6, but is sufficiently small to be expressed in an AAV vector for gene transfer. 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.