Sacubitril/Valsartan Improves Left Ventricular Function in Chronic Pressure Overload Independent of Intact Cyclic Guanosine Monophosphate-dependent Protein Kinase I Alpha Signaling

J Card Fail. 2020 Sep;26(9):769-775. doi: 10.1016/j.cardfail.2020.04.011. Epub 2020 May 25.

Abstract

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.

MeSH terms

  • Aminobutyrates* / administration & dosage
  • Animals
  • Biphenyl Compounds* / administration & dosage
  • Cyclic GMP-Dependent Protein Kinase Type I / metabolism
  • Drug Combinations
  • Guanosine Monophosphate / metabolism
  • Heart Failure* / drug therapy
  • Heart Failure* / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Random Allocation
  • Valsartan* / administration & dosage
  • Ventricular Function, Left* / drug effects

Substances

  • Aminobutyrates
  • Biphenyl Compounds
  • Drug Combinations
  • Valsartan
  • Guanosine Monophosphate
  • Cyclic GMP-Dependent Protein Kinase Type I
  • sacubitril and valsartan sodium hydrate drug combination