Background

Combined angiotensin receptor/neprilysin inhibition with sacubitril/valsartan (Sac/Val) has emerged as a therapy for heart failure. The presumed mechanism of benefit is through prevention of natriuretic peptide degradation, leading to increased cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) signaling. However, the specific requirement of PKG for Sac/Val effects remains untested.

Methods and Results

We examined Sac/Val treatment in mice with mutation of the cGMP-dependent protein kinase I (PKGI)α leucine zipper domain, which is required for cGMP-PKGIα antiremodeling actions in vivo. Wild-type (WT) or PKG leucine zipper mutant (LZM) mice were exposed to 56-day left ventricular (LV) pressure overload by moderate (26G) transaortic constriction (TAC). At day 14 after TAC, mice were randomized to vehicle or Sac/Val by oral gavage. TAC induced the same degree of LV pressure overload in WT and LZM mice, which was not affected by Sac/Val. Although LZM mice, but not WT, developed LV dilation after TAC, Sac/Val improved cardiac hypertrophy and LV fractional shortening to the same degree in both the WT and LZM TAC mice.

Conclusion

These findings indicate the beneficial effects of Sac/Val on LV structure and function in moderate pressure overload. The unexpected finding that PKGIα mutation does not abolish the Sac/Val effects on cardiac hypertrophy and on LV function suggests that signaling other than natriuretic peptide– cGMP–PKG mediates the therapeutic benefits of neprilysin inhibition in heart failure.

中文翻译：

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沙库巴曲/缬沙坦改善慢性压力超负荷的左心室功能，独立于完整的环状鸟苷单磷酸依赖性蛋白激酶 I α 信号。

背景

血管紧张素受体/脑啡肽酶抑制剂联合沙库巴曲/缬沙坦 (Sac/Val) 已成为治疗心力衰竭的一种疗法。推测的获益机制是通过防止利钠肽降解，导致环磷酸鸟苷 (cGMP) 依赖性蛋白激酶 (PKG) 信号传导增加。然而，PKG 对 Sac/Val 效应的具体要求仍未经过测试。

方法和结果

我们检查了具有 cGMP 依赖性蛋白激酶 I (PKGI)α 亮氨酸拉链结构域突变的小鼠的 Sac/Val 治疗，这是体内 cGMP-PKGIα 抗重塑作用所必需的。野生型 (WT) 或 PKG 亮氨酸拉链突变体 (LZM) 小鼠通过中度 (26G) 经主动脉收缩 (TAC) 暴露于 56 天的左心室 (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赋形剂或 Sac/Val。TAC 在 WT 和 LZM 小鼠中诱导了相同程度的 LV 压力超负荷，这不受 Sac/Val 的影响。尽管 LZM 小鼠（而非 WT）在 TAC 后发生了 LV 扩张，但 Sac/Val 在 WT 和 LZM TAC 小鼠中以相同程度改善了心脏肥大和 LV 部分缩短。

结论

这些发现表明 Sac/Val 对中度压力超负荷下 LV 结构和功能的有益影响。PKGIα 突变不会消除 Sac/Val 对心脏肥大和 LV 功能的影响这一意外发现表明，除利钠肽-cGMP-PKG 之外的信号传导介导了脑啡肽酶抑制对心力衰竭的治疗益处。