The Hippo in the Clinic

Visual Abstract
Highlights • YAP, a terminal effector of the Hippo signaling pathway, is activated in cardiomyocytes in response to high-fat diet consumption in mice and diabetes in patients. • Long-term activation of YAP in response to high-fat diet consumption is detrimental for the heart in the presence of pressure overload. • Detrimental effects of YAP during pressure overload are mediated through activation of a positive feedback loop, consisting of YAP, TEAD1, and OSM, and consequent dedifferentiation of cardiomyocytes. • Chemical inhibitors of YAP, TEAD1, or OSM may be effective in treating patients who have diabetes, high blood pressure, and metabolic syndrome to prevent heart failure syndromes.
Summary Patients with diabetes are more prone to developing heart failure in the presence of high blood pressure than those without diabetes. Yes-associated protein (YAP), a key effector of the Hippo signaling pathway, is persistently activated in diabetic hearts, and YAP plays an essential role in mediating the exacerbation of heart failure in response to pressure overload in the hearts of mice fed a high-fat diet. YAP induced dedifferentiation of cardiomyocytes through activation of transcriptional enhancer factor 1 (TEAD1), a transcription factor. Thus, YAP and TEAD1 are promising therapeutic targets for diabetic patients with high blood pressure to prevent the development of heart failure.