Sacubitril/valsartan improves LV function in chronic pressure overload independently of intact cGMP-dependent protein kinase I alpha signaling

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.