Sacubitril/Valsartan Improves Left Ventricular Function in Chronic Pressure Overload Independent of Intact Cyclic Guanosine Monophosphate-dependent Protein Kinase I Alpha Signaling.
Sacubitril/Valsartan Improves Left Ventricular Function in Chronic Pressure Overload Independent of Intact Cyclic Guanosine Monophosphate-dependent Protein Kinase I Alpha Signaling.
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DOI：
10.1016/j.cardfail.2020.04.011
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发表时间：
2020-09
影响因子：
6
通讯作者：
Blanton RM
中科院分区：
文献类型：
--
作者：
Tam K;Richards DA;Aronovitz MJ;Martin GL;Pande S;Jaffe IZ;Blanton RM
联合血管紧张素受体/脑啡肽酶抑制剂与沙库巴曲/缬沙坦已成为心力衰竭（HF）的治疗方法。推测的获益机制是通过预防利尿钠肽（NP）降解，导致cGMP依赖性蛋白激酶（PKG）信号传导增加。然而，PKG对沙库巴曲/缬沙坦效应的具体要求尚未得到检验。我们在PKGIα亮氨酸拉链结构域突变的小鼠中研究了沙库巴曲/缬沙坦治疗，PKGIα亮氨酸拉链结构域是体内cGMP-PKGIα抗重塑作用所必需的。WT或PKG亮氨酸拉链突变体（LZM）小鼠通过中度（26 Gauge）经主动脉缩窄（TAC）暴露于56天LV压力超负荷。在TAC后第14天，通过口服管饲法将小鼠随机分配至媒介物或沙库巴曲/缬沙坦。TAC在WT和LZM小鼠中诱导相同程度的LV压力超负荷，这不受沙库巴曲/缬沙坦的影响。尽管LZM小鼠（而非WT）在TAC后出现LV扩张，但沙库巴曲缬沙坦在WT和LZM TAC小鼠中改善心脏肥大和LV缩短分数的程度相同。这些结果表明沙库巴曲/缬沙坦对中度压力超负荷时左室结构和功能的有益作用。PKGIα突变不能消除沙库巴曲/缬沙坦对心脏肥大和LV功能的影响，这一意外发现表明，NP-cGMP-PKG以外的信号传导介导了脑啡肽酶抑制在HF中的治疗益处。
Combined angiotensin receptor/neprilysin inhibition with sacubitril/valsartan has emerged as a therapy for heart failure (HF). The presumed mechanism of benefit is through prevention of natriuretic peptide (NP) degradation, leading to increased cGMP-dependent protein kinase (PKG) signaling. However, the specific requirement of PKG for sacubitril/valsartan effects remains untested. We examined sacubitril/valsartan treatment in mice with mutation of the PKGIα leucine zipper domain, which is required for cGMP-PKGIα anti-remodeling actions in vivo. WT or PKG Leucine Zipper Mutant (LZM) mice were exposed to 56-day LV pressure overload by moderate (26 Gauge) transaortic constriction (TAC). At day 14 post-TAC, mice were randomized to vehicle or sacubitril/valsartan by oral gavage. TAC induced the same degree of LV pressure overload in WT and LZM mice, which was not affected by sacubitril/valsartan. Though LZM mice, but not WT, developed LV dilation post-TAC, sacubitril valsartan improved cardiac hypertrophy and LV fractional shortening to the same degree in both the WT and LZM TAC mice. These ladings indicate beneficial effects of sacubitril/valsartan on LV structure and function in moderate pressure overload. The unexpected finding that PKGIα mutation does not abolish the sacubitril/valsartan effects on cardiac hypertrophy and on LV function suggests that signaling other than NP-cGMP-PKG mediates the therapeutic benefits of neprilysin inhibition in HF.
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影响因子：
6
作者：
Suematsu, Yasunori;Jing, Wanghui;Moradi, Hamid
通讯作者：
Moradi, Hamid
影响因子：
4.6
作者：
Richards, Daniel A.;Aronovitz, Mark J.;Blanton, Robert M.
通讯作者：
Blanton, Robert M.
分子筛选将心脏肌球蛋白结合蛋白-C鉴定为蛋白激酶G-Iα底物。
DOI：
10.1161/circheartfailure.115.002308
发表时间：
2015-11
期刊：
Circulation. Heart failure
影响因子：
--
作者：
Thoonen R;Giovanni S;Govindan S;Lee DI;Wang GR;Calamaras TD;Takimoto E;Kass DA;Sadayappan S;Blanton RM
通讯作者：
Blanton RM
DOI：
10.1161/circheartfailure.113.000575
发表时间：
2013-11
期刊：
Circulation. Heart failure
影响因子：
--
作者：
Kong Q;Blanton RM
通讯作者：
Blanton RM
影响因子：
20.1
作者：
Vettel, Christiane;Lindner, Marta;El-Armouche, Ali
通讯作者：
El-Armouche, Ali