Synoviolin-Mediated Regulation of Protein Synthesis Protects Against Pathological Cardiac Hypertrophy and Remodeling

Objective: Cardiac hypertrophy and remodeling induced by pressure overload are major contributors to heart failure progression. These processes lead to cellular stress and protein misfolding, activating the unfolded protein response (UPR) in the endoplasmic reticulum (ER). We investigated whether synoviolin (Syvn1), an ER-resident E3 ubiquitin ligase, which we previously found prevents the progression to heart failure in the setting of pressure overload, regulates protein synthesis and cardiac myocyte size during hypertrophic stress. Hypothesis: We hypothesized that Syvn1 modulates protein synthesis to mitigate pathological cardiac hypertrophy, thereby preventing the progression to heart failure. Methods and Results: We performed in vitro studies using neonatal rat ventricular myocytes (NRVMs), manipulating Syvn1 expression through adenovirus-mediated overexpression or knockdown, and treating the NRVMs with phenylephrine (PE) to induce hypertrophy. In vivo, pressure overload-induced hypertrophy was modeled in mice using transverse aortic constriction (TAC) surgery, followed by cardiac myocyte-targeted Syvn1 delivery via adeno-associated virus 9 (AAV9). Our results showed that Syvn1 overexpression in NRVMs reduced protein synthesis and myocyte hypertrophy induced by PE treatment, accompanied by activation of the protein kinase R-like ER kinase (PERK) pathway, one of the three major branches in the UPR, and the only one modulating protein synthesis. These effects were reversed by selective PERK inhibition. Conversely, Syvn1 knockdown in NRVMs enhanced protein synthesis and cardiac myocyte size upon PE treatment compared to PE treatment alone, which could not be suppressed by activation of the PERK pathway. Additionally, Syvn1 overexpression increased expression of the translationally regulated transcription factor named Activating Transcription Factor 4 (ATF4) downstream of PERK, along with its stress-adaptive genes, supporting a role for Syvn1 in regulating protein synthesis under stress. In mice, therapeutic delivery of AAV9-Syvn1 post TAC surgery reduced myocyte size, mitigated pathological remodeling, and preserved cardiac function. Conclusions: Syvn1 regulates protein synthesis and attenuates maladaptive cardiac remodeling by activating the PERK/ATF4 pathway, revealing a novel anti-hypertrophic mechanism. Targeting Syvn1 may offer a therapeutic strategy to prevent heart failure progression. Supported by UA Postdoc Grant, BIO5 Fellowship (M.A.), NIH HL170223, UA Career Award, UA COM-Phoenix, and DZHK (German Centre for Cardiovascular Research) (S.D.). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.