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Updated: Jun 3, 2025
Technique of Minimally Invasive Transverse Aortic Constriction in Mice for Induction of Left Ventricular Hypertrophy
Published on: September 25, 2017
Sacubitril/valsartan reduces proteasome activation and cardiomyocyte area in an experimental mouse model of
Moritz Meyer-Jens1,2, Kristin Wenzel3,4, Karina Grube3,4
1Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
Insights
Sacubitril/valsartan (Sac/Val) improves heart function by normalizing proteasome activity in heart failure models. The drug reduces cardiac hypertrophy and fibrosis, with sacubitril showing key therapeutic effects.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Pharmacology
Background:
- Sacubitril/valsartan (Sac/Val) is a key treatment for heart failure (HF).
- The precise mechanisms behind Sac/Val's beneficial effects remain unclear.
- Proteolytic systems like the ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway (ALP) are implicated in cardiac remodeling.
Purpose of the Study:
- To investigate the impact of Sac/Val on the UPS and ALP in cardiac hypertrophy.
- To elucidate the specific contributions of sacubitril and valsartan to Sac/Val's therapeutic actions.
Main Methods:
- Utilized a mouse model of pressure overload induced by transverse aortic constriction (TAC).
- Employed human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with endothelin-1 (ET1) to model cardiac hypertrophy.
- Assessed cardiac function, hypertrophy, fibrosis, and the expression/activity of UPS and ALP markers.
Main Results:
- TAC mice exhibited declining cardiac function, which was improved by Sac/Val treatment.
- Sac/Val attenuated cardiac hypertrophy and fibrosis in TAC mice.
- Proteasome activity was elevated in TAC mice and normalized by Sac/Val; ALP markers showed no significant changes.
- In hiPSC-CMs, Sacubitril (alone or with valsartan) prevented ET1-induced hypertrophic gene expression and proteomic changes, while valsartan alone did not.
Conclusions:
- Sacubitril/valsartan effectively improves cardiac function and reduces pathological remodeling in a pressure overload model.
- The study highlights the normalization of proteasome activity as a key mechanism.
- Evidence suggests that the therapeutic benefits of Sac/Val largely stem from the sacubitril component.
Abstract:
Sacubitril/valsartan (Sac/Val) belongs to the group of angiotensin receptor-neprilysin inhibitors and has been used for the treatment of heart failure (HF) for several years. The mechanisms that mediate the beneficial effects of Sac/Val are not yet fully understood. In this study we investigated whether Sac/Val influences the two proteolytic systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP), in a mouse model of pressure overload induced by transverse aortic constriction (TAC) and in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated with endothelin-1 (ET1) serving as a human cellular model of hypertrophy. TAC mice showed a continuous decline in cardiac function starting from day 14 after surgery. Administration of Sac/Val for 6 weeks counteracted the deterioration of cardiac function and attenuated hypertrophy and fibrosis in TAC mice. The expression of ALP key markers did not differ between the groups. Proteasome activity was higher in TAC mice and normalized by Sac/Val. In hiPSC-CMs, all treatments (Sac, Val or Sac/Val) normalized mean cell area. However, Sac alone or in combination with Val, but not Val alone prevented ET1-induced hypertrophic gene program and proteomic changes. In conclusion, Sac/Val normalized proteasome activity, improved cardiac function and reduced fibrosis and hypertrophy in TAC mice. Molecular analysis in hiPSC-CMs suggests that a major part of the beneficial effects of Sac/Val is derived from the Sac action rather than from Val.
