Victor Moura

Although STIP1 is expressed in the heart and known for neuroprotection, its cardiac role remains undefined. We show that STIP1 is reduced in failing human hearts and that its deficiency in mice impairs resilience to adrenergic overload. Mechanistically, STIP1 loss disrupts the protein synthesis required for cardiomyocyte hypertrophy, positioning this co-chaperone as a hub of the heart’s adaptive response to injury. Clinically, reduced STIP1 in heart failure may worsen dysfunction, underscoring its relevance to disease.

Background: Stress-inducible phosphoprotein 1 (STIP1) is a co-chaperone involved in neuronal proteostasis and stress resilience. Although expressed in the heart, its role remains undefined. We assessed whether STIP1 deficiency impacts cardiac physiology and stress responses.Methods: STIP1 expression was analyzed in cardiac tissue from heart failure patients. Haploinsufficient STIP1 mice (STIP1+/−) received 7 days of isoproterenol (ISO) to induce cardiac injury, followed by proteomics, histology, and western blot analysis. In vitro, neonatal rat cardiomyocytes (NRCMs) underwent STIP1 or prion protein (PrPC) silencing and were evaluated using molecular assays and total internal reflection fluorescence (TIRF) microscopy.Results: STIP1 levels were reduced in cardiac tissue from heart failure patients, a pattern mirrored in STIP1+/- mice. While STIP1+/- hearts developed normally, ISO exposure led to increased inflammation and fibrosis compared with wild-type. Despite elevated injury markers, STIP1+/- cardiomyocytes failed to undergo hypertrophy in response to ISO. Proteomic profiling identified impaired protein synthesis as the dominant signature in STIP1+/-/ISO hearts, explaining the blunted hypertrophic response. To define STIP1´s contribution to hypertrophy, we silenced STIP1 in NRCMs. Recapitulating in vivo findings, STIP1 silencing blocked ISO‑induced hypertrophy, and also inhibited AngII and phenylephrine hypertrophic responses. Consistent with proteomics, ISO failed to increase protein synthesis or eIF4 expression in STIP1-deficient NRCMs. STIP1 localized to exocytic vesicles, consistent with its secretion visualized by TIRF. Co‑immunoprecipitation confirmed its interaction with PrPC. PrPC silencing abrogated ISO- or AngII-induced hypertrophy, phenocopying STIP1-deficiency.Conclusion: STIP1 engages PrPC in cardiomyocytes to form a receptor‑linked axis that drives pathological hypertrophy through protein‑synthesis–dependent mechanisms.