Anti-fibrotic cardioprotection of berberine via down-regulating myocardial IGF-1 receptor-regulated MMP-2/9 expression in diabetic rats.
Am J Physiol Heart Circ Physiol. 2018 Jun 29. Epub 2018 Jun 29. PMID: 29957017
Diabetic cardiac fibrosis increases ventricular stiffness and facilitates occurrence of diastolic dysfunction. Our previous studies have shown that berberine, a natural alkaloid, attenuates cardiac ischemic/reperfusion injury in diabetic rats. The aim of present study was to investigate the effects of long-term berberine treatment on cardiac remodeling in diabetic rats and the underlying mechanisms. Diabetic rats induced by low dose of streptozotocin injection combined with 8-week high-fat diet displayed significant cardiac matrix collagen deposition and dysfunction, while berberine administration (200 mg•kg•day, gavage, 4 weeks) significantly ameliorated cardiac fibrosis and dysfunction and reduced cardiac IGF-1 receptor (IGF-1R) expression in diabetic rats. Interestingly, IGF-1R expression was up-regulated in cardiac fibroblasts isolated from diabetic hearts or cultured in high glucose condition (30 mM). High glucose treatment or IGF-1R overexpression increased matrix metalloproteinase (MMP)-2/9 expression,α-smooth muscle actin (α-SMA) and collagen I expression in cardiac fibroblasts. In contrast, berberine treatment significantly inhibited IGF-1R expression and exerted an anti-fibrotic effect in high glucose-cultured cardiac fibroblasts, as manifested by decreased MMP-2/9, a-SMA and collagen I expression, while IGF-1R siRNA plus berberine treatment did not further enhance this anti-fibrotic effect compared with berberine treatment alone. Taken together, long-term berberine treatment ameliorates cardiac fibrosis and dysfunction by down-regulating IGF-1R expression in cardiac fibroblasts, and subsequently reducing MMP-2/9, a-SMA and collagen I expression in diabetic hearts. The findings suggest berberine's therapeutic potential for diabetic cardiomyopathy associated with cardiac fibrosis.