VMP1 enhances autophagy to mitigate cardiac fibroblast activation and reduce post-ischemia-reperfusion fibrosis

Background

Myocardial ischemia-reperfusion (I/R) injury contributes significantly to cardiac fibrosis, yet the regulatory mechanisms linking autophagy to fibroblast activation remain unclear. Vacuole membrane protein 1 (VMP1), an endoplasmic reticulum protein critical for autophagy initiation, has not been explored in this context.

Methods

We established a mouse model of I/R injury through left anterior descending (LAD) artery ligation, followed by reperfusion. Cardiac function was evaluated using echocardiography, while fibrosis and infarct size were assessed via Masson's trichrome and TTC staining. In vitro, primary cardiac fibroblasts were isolated and treated with TGF-β1 and PDGF-BB to simulate fibroblast activation. VMP1 was overexpressed using adenoviral vectors to investigate its effect on fibroblast activation, autophagic flux, and extracellular matrix (ECM) deposition.

Results

VMP1 expression was markedly downregulated in I/R-injured hearts and TGF-β1-stimulated fibroblasts. Overexpression of VMP1 enhanced autophagic flux (increased LC3-II/LC3-I, decreased p62) and suppressed fibroblast activation, reducing α-SMA and collagen I levels. Mechanistically, VMP1 inhibited mTOR phosphorylation, and alleviated endoplasmic reticulum stress.

Conclusions

VMP1 mitigates cardiac fibrosis by enhancing autophagy and restraining fibroblast-to-myofibroblast transition, highlighting its therapeutic potential for post-I/R injury. Further studies should explore clinical translation of VMP1-targeted strategies.