Sacubitril/Valsartan Act on Exosomes to Facilitate Heart Repair

By Adrienne Mueller, PhD
July 2, 2020

Heart failure is a major source of hospitalizations and deaths worldwide. When the heart cells or cardiomyocytes, are damaged due to heart failure, cellular signaling pathways are activated to help repair the damage. Two major pathways involved in cardiomyocyte health are the renin-angiotensin-aldosterone pathway and the natriuretic pathway. Activating or inhibiting these pathways influences cardiomyocyte repair.

The drug sacubitril/valsartan (Entresto^TM) acts on these pathways and demonstrated significantly increased survival of heart failure patients. This novel compound improves heart health by facilitating vasodilation, reducing the extracellular volume, and decreasing both tissue scarring and the unhealthy increase in cardiomyocyte cell size (hypertrophy) that occur after heart failure. A key question, however, is what is the molecular mechanism that mediates sacubitril/valsartan’s effects? A novel possibility is that sacubitril/valsartan could influence cardiomyocyte health through altered production or content of cardiomyocyte exosomes. Exosomes are vesicles, filled with small molecules such as microRNAs, that cells release to communicate with other nearby cells to maintain tissue homeostasis.

A team of CVI-affiliated scientists led by first-author Evgeniya Vaskova, PhD, and senior-author Phillip Yang, MD, addressed the question of whether exosomes were involved in mediating the therapeutic effects of sacubitril/valsartan in a recent study published in the Journal of the American Heart Association. First, they tested the effects of sacubitril/valsartan on stem cell-derived cardiomyocytes (iPSC-CMs) that either had or had not been deprived of oxygen - mimicking cardiac ischemia.  They also looked at the effect of the drug on cardiomyocyte health in rodents with heart attacks. In both experiments, treatment with sacubitril/valsartan improved cardiomyocyte function and reduced scaring and hypertrophy. Second, they determined that treatment with sacubitril/valsartan caused heart cells, both iPSC-CMs and cardiomyocytes in rodents with heart attacks, released significantly more exosomes. Studying these exosomes revealed that their payload contained reduced amount of specific microRNA: miR-181a. The authors went on to show that inhibiting the expression of miR-181a in rodents with heart attacks led to healthier hearts. Their study therefore demonstrated a novel molecular mechanism underlying sacubitril/valsartan’s therapeutic effects: 1) increased exosome release and 2) reduced microRNA miR-181a in the exosomes.

Not only does this study show a novel mechanism for drug action that will inform development of future pharmacotherapies, but it indicates that miR-181a specifically, which is detectable in circulating blood, could be used as a biomarker to indicate heart failure progression and to predict drug response.

Other Stanford Cardiovascular Institute members who contributed to this study are Gentaro Ikeda, Yuko Tada, Christine Wahlquist and Marc Mercola.