Abstract Body: Stimulation of endogenous cardiomyocyte (CM) proliferation has emerged as a promising strategy for cardiac repair post myocardial infarction (MI). We previously found that miR-411 promotes CM proliferation and cardiac function via YAP activation, a key Hippo pathway regulator. However, the mechanism of miR-411–mediated Hippo inhibition remains unclear. Here, our study aims to address this knowledge gap and assess whether modulating miR-411 target genes could improve cardiac function post-MI.
We identified the serotonin transporter gene (SERT) as a key miR-411 target through screening bioinformatically predicted target genes. Expression of SERT was significantly reduced in miR-411 overexpressing CMs and myocardium and a luciferase reporter assay confirmed direct miR-411 binding to exon 4 of the SERT mRNA. Moreover, SERT downregulation enhances YAP activity, leading to increased CM proliferation and survival in vitro. Mechanistically, we found that SERT knockdown leads to serotonin receptor activation, subsequently increasing ROCK1 and YAP activity (Fig 1). Western blot analysis of SERT-deficient CMs revealed elevated phosphorylation of MYPT1, a downstream target of ROCK1, confirming that SERT modulates YAP via ROCK1 signalling.
To assess the effects of SERT modulation on post-MI cardiac function in vivo, we generated AAV9 vectors encoding shRNA to knock down SERT expression (AAV9-shSERT), driven by the CM-specific cTnT promoter. Following ischemia-reperfusion (I/R) injury in mice, intravenous administration of AAV9-shSERT resulted in significant reductions in ejection fraction and fractional shortening at 5 weeks post-I/R, as measured by echocardiography. Moreover, SERT knockdown led to increased CM size and fibrosis, indicating that CM-specific SERT depletion worsened, rather than improved, left ventricular function post-I/R.
In conclusion, our study reveals a novel role for SERT in cardiac remodelling post I/R. While SERT downregulation enhances YAP activity in vitro, it unexpectedly exacerbates LV dysfunction and fibrosis in vivo. Ongoing investigations aim to determine whether increased ROCK1 activity is responsible for the observed adverse effects, given previous reports linking ROCK1 activation to fibrosis and hypertrophic decompensation in ischemic hearts.