Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain (C1C2) Attenuates Deleterious Effects of Pressure Overload.
Cardiac-Directed Expression of Adenylyl Cyclase Catalytic Domain (C1C2) Attenuates Deleterious Effects of Pressure Overload.
复制标题
腺苷酸环化酶催化结构域 (C1C2) 的心脏定向表达可减轻压力过载的有害影响。
DOI：
10.1089/hum.2018.176
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发表时间：
2019
影响因子：
4.2
通讯作者：
Hammond,HKirk
中科院分区：
文献类型：
--
作者：
Tan,Zhen;Giamouridis,Dimosthenis;Lai,NChin;Kim,YoungChul;Guo,Tracy;Xia,Bing;Gao,MeiHua;Hammond,HKirk
通过融合腺苷酸环化酶6型（AC 6）的细胞内C1和C2片段构建的融合蛋白（C1 C2）保留了AC 6表达的有益效果，而不增加环腺苷酸的产生。心脏定向C1 C2表达在压力超负荷中的作用尚不清楚。在C1 C2小鼠和转基因阴性（TG-）小鼠中通过横向主动脉缩窄（TAC）诱导左心室（LV）压力超负荷。TAC后4周，测量左室收缩功能和舒张功能，并评估Ca 2+处理。TAC后四周，TG-动物显示LV峰值+dP/dt降低。C1 C2小鼠中的LV峰值+dP/dt与正常小鼠的LV峰值+dP/dt在统计学上不可区分，并且高于TAC后4周在TG-小鼠中观察到的LV峰值+dP/dt（p= 0.02），尽管类似且实质性的心脏肥大。除了体内较高的LV峰值+dP/din外，C1 C2小鼠的心肌细胞显示出较短的达峰时间Ca 2+瞬时振幅（p= 0.002）和细胞溶质Ca 2+下降的时间常数降低（Tau;p= 0.003）。C1 C2心肌细胞肌节缩短率（p<0.02）和肌节缩短率（p<0.03）增加。在C1 C2肌细胞中，肌丝对Ca 2+的敏感性在收缩期（p= 0.02）和收缩素（p= 0.04）增加。这些发现表明与C1 C2表达相关的Ca 2+处理增强。对Ca 2+处理和LV功能的有利作用与LV SERCA 2a蛋白含量增加（p= 0.015）和LV纤维化减少（p= 0.008）相关。心脏定向的C1 C2表达改善了压力超负荷时的Ca 2+处理并增加了LV收缩功能。这些数据为进一步探索C1 C2基因转移作为心力衰竭的潜在治疗方法提供了理论基础。
A fusion protein (C1C2) constructed by fusing the intracellular C1 and C2 segments of adenylyl cyclase type 6 (AC6) retains beneficial effects of AC6 expression, without increasing cyclic adenosine monophosphate generation. The effects of cardiac-directedC1C2expression in pressure overload is unknown. Left ventricular (LV) pressure overload was induced by transverse aortic constriction (TAC) in C1C2 mice and in transgene negative (TG–) mice. Four weeks after TAC, LV systolic function and diastolic function were measured, and Ca2+ handling was assessed. Four weeks after TAC, TG– animals showed reduced LV peak +dP/dt. LV peak +dP/dt in C1C2 mice was statistically indistinguishable from that of normal mice and was higher than that seen in TG– mice 4 weeks after TAC (p= 0.02), despite similar and substantial cardiac hypertrophy. In addition to higher LV peak +dP/dtin vivo, cardiac myocytes from C1C2 mice showed shorter time-to-peak Ca2+ transient amplitude (p= 0.002) and a reduced time constant of cytosolic Ca2+ decline (Tau;p= 0.003). Sarcomere shortening fraction (p< 0.03) and the rate of sarcomere shortening (p< 0.02) increased in C1C2 cardiac myocytes. Myofilament sensitivity to Ca2+ was increased in systole (p= 0.02) and diastole (p= 0.04) in C1C2 myocytes. These findings indicate enhanced Ca2+ handling associated withC1C2expression. Favorable effects on Ca2+ handling and LV function were associated with increased LV SERCA2a protein content (p= 0.015) and reduced LV fibrosis (p= 0.008). Cardiac-directedC1C2expression improves Ca2+ handling and increases LV contractile function in pressure overload. These data provide a rationale for further exploration of C1C2 gene transfer as a potential treatment for heart failure.