Involvement of Fibulin-5 in endothelial to mesenchymal transition leading to cardiac fibrosis during metabolic syndrome.

BACKGROUND

Cardiac fibrosis is a hallmark of metabolic syndrome, a condition linked to Western lifestyles and high cardiovascular risk. We previously demonstrated that dietary sodium restriction prevents cardiac fibrosis and remodeling in a rat model of metabolic syndrome through reduced macrophage infiltration. Here, we investigate genes involved in endothelial-to-mesenchymal transition (EndoMT), a key process in cardiac fibrosis.

METHODS

Metabolic syndrome was induced in rats by high-fructose feeding combined with angiotensin II infusion. EndoMT was assessed in left ventricles and in vitro using TGF-β2-treated human aortic (HAEC) and umbilical vein endothelial cells (HUVEC) via immunofluorescence, western blotting, and RT-qPCR. Lentiviral shRNA was used to knock down target genes.

RESULTS

Sodium restriction reduced vascular EndoMT in rat left ventricles and downregulated several candidate genes. In vitro, Fibulin-5, a matricellular protein, was markedly upregulated during EndoMT. Silencing Fibulin-5 prevented TGF-β2-induced EndoMT in HAEC and HUVEC, indicating its essential role. Mechanistically, Fibulin-5 modulated SMAD2/3, ERK1/2, and p38 MAPK pathways. In vivo, Fibulin-5 expression was significantly reduced in aortic intima and plasma of sodium-restricted rats.

CONCLUSION

Fibulin-5 emerges as a potential mediator of vascular EndoMT and cardiac fibrosis through TGF-β signaling modulation. Dietary sodium restriction mitigates this process, highlighting Fibulin-5 as a potentially important contributor in metabolic syndrome-related cardiac remodeling.