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Published on: April 8, 2013
Sacubitril/Valsartan Improves Left Ventricular Function in Chronic Pressure Overload Independent of Intact Cyclic
Kelly Tam1, Daniel A Richards1, Mark J Aronovitz1
1Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts.
Insights
Sacubitril/valsartan benefits heart failure by improving cardiac function. However, its therapeutic effects on cardiac hypertrophy and function do not depend on cyclic guanosine monophosphate-dependent protein kinase I alpha signaling.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Sacubitril/valsartan (Sac/Val) is a novel therapy for heart failure.
- Its mechanism is thought to involve increased cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG) signaling.
- The necessity of PKG for Sac/Val's therapeutic effects has not been previously investigated.
Purpose of the Study:
- To investigate the role of cGMP-dependent protein kinase I alpha (PKGIα) in mediating the effects of Sac/Val.
- To determine if PKGIα is essential for Sac/Val's beneficial actions in a pressure overload model of heart failure.
Main Methods:
- Mice with a mutation in the PKGIα leucine zipper domain (LZM) and wild-type (WT) littermates were subjected to transaortic constriction (TAC) for 56 days to induce left ventricular (LV) pressure overload.
- Following 14 days of TAC, mice were randomized to receive either vehicle or Sac/Val.
- Cardiac structure and function were assessed.
Main Results:
- TAC induced similar LV pressure overload in both WT and LZM mice, unaffected by Sac/Val.
- LZM mice developed LV dilation post-TAC, unlike WT mice.
- Sac/Val treatment improved cardiac hypertrophy and LV fractional shortening to a similar extent in both WT and LZM mice.
Conclusions:
- Sac/Val demonstrates beneficial effects on LV structure and function in moderate pressure overload.
- The therapeutic benefits of Sac/Val in cardiac hypertrophy and function are independent of PKGIα.
- These findings suggest that neprilysin inhibition's beneficial effects in heart failure may be mediated by pathways other than natriuretic peptide-cGMP-PKG signaling.
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.
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