The serotonin receptor 2b (5-HT_2B) modulates heart remodeling following myocardial infarction via regulation of Hippo pathway

Myocardial infarction (MI) is a leading cause of death globally. Following MI, the heart undergoes remodeling leading to heart failure. The Hippo pathway is a major regulator of cell growth and survival in cardiomyocytes. Here, we show that serotonin receptor 2B (5-HT_2B) regulates the Hippo pathway in cardiomyocytes and modulates heart remodeling following MI. 5-HT_2B expression significantly enhanced the Hippo pathway effector Yes-associated protein (YAP) activity resulting in increased cardiomyocyte proliferation and decreased apoptosis. However, transgenic mice overexpressing 5-HT_2B in cardiomyocytes had a lower survival rate post-MI. Conversely, modified mRNA (modRNA)-mediated transient 5-HT_2B expression in the heart was sufficient to inhibit post-MI remodeling. Pharmacological screening of serotonergic compounds identified SB204741 as a modulator of the Hippo/YAP pathway in cardiomyocytes. SB204741 has been shown to protect the heart from adverse remodeling post-MI. Our findings identify 5-HT_2B as a regulator of the Hippo pathway that can be targeted to improve cardiac phenotype following MI.