Exosomes are small extracellular vesicles that function as intercellular messengers and effectors. Exosomal cargo contains small regulatory molecules, including miRNAs, mRNAs, lncRNAs, and small peptides modulated by different pathological stimuli to the cells. One of the main mechanisms of drug therapy action may be the altered production and content of the exosomes.
We studied the effects on exosome production and content by neprilysin inhibitor/angiotensin receptor blockers, sacubitril/valsartan, and valsartan alone, using human‐induced pluripotent stem cell‐derived cardiomyocytes under normoxic and hypoxic injury model in vitro, and assessed for physiologic correlation using an ischemic myocardial injury rodent model in vivo. We demonstrated that the treatment with sacubitril/valsartan and valsartan alone resulted in increased exosome production by induced pluripotent stem cell‐derived cardiomyocytes in vitro in both conditions as well as in the rat plasma in vivo. Next‐generation sequencing of these exosomes exhibited downregulation of the expression of rno‐miR‐181a in the sacubitril/valsartan treatment group. In vivo studies employing the chronic rodent myocardial injury model demonstrated that miR‐181a antagomir has a beneficial cardiac function effect. Subsequently, immunohistochemical and molecular studies suggested that the downregulation of miR‐181a resulted in the attenuation of myocardial fibrosis and hypertrophy, restoring the injured rodent heart after myocardial infarction.
We demonstrate that an additional mechanism of action of the pleiotropic effects of sacubitril/valsartan may be mediated by the modulation of the exosome payload’s miRNA expression level.
In conclusion, our study represents novel data on additional molecular mechanisms of action of the pleiotropic effects of sacubitril/valsartan in a rodent model of chronic myocardial injury. The pharmacologic effects on exosome production and molecular payload describe a potentially novel mechanism of their underlying physiological mechanism of action and may provide an alternative and innovative platform for pharmacogenomics.
Ref: https://www.ahajournals.org/doi/10.1161/JAHA.119.015640
