title: Doxazosin Stimulates Galectin-3 Expression and Collagen Synthesis in HL-1 Cardiomyocytes Independent of Protein Kinase C Pathway.
abstract: Doxazosin, a drug commonly prescribed for hypertension and prostate disease, increases heart failure risk. However, the underlying mechanism remains unclear. Galectin-3 is an important mediator that plays a pathogenic role in cardiac hypertrophy and heart failure. In the present study, we investigated whether doxazosin could stimulate galectin-3 expression and collagen synthesis in cultured HL-1 cardiomyocytes. We found that doxazosin dose-dependently induced galectin-3 protein expression, with a statistically significant increase in expression with a dose as low as 0.01 μM. Doxazosin upregulated collagen I and α-smooth muscle actin (α-SMA) protein levels and also induced apoptotic protein caspase-3 in HL-1 cardiomyocytes. Although we previously reported that activation of protein kinase C (PKC) stimulates galectin-3 expression, blocking the PKC pathway with the PKC inhibitor chelerythrine did not prevent doxazosin-induced galectin-3 and collagen expression. Consistently, doxazosin treatment did not alter total and phosphorylated PKC. These results suggest that doxazosin-stimulated galectin-3 is independent of PKC pathway. To determine if the α1-adrenergic pathway is involved, we pretreated the cells with the irreversible α-adrenergic receptor blocker phenoxybenzamine and found that doxazosin-stimulated galectin-3 and collagen expression was similar to controls, suggesting that doxazosin acts independently of α1-adrenergic receptor blockade. Collectively, we show a novel effect of doxazosin on cardiomycytes by stimulating heart fibrosis factor galectin-3 expression. The mechanism of action of doxazosin is not mediated through either activation of the PKC pathway or antagonism of α1-adrenergic receptors.
authors.affiliation: Cardiovascular Center, The Fourth Affiliated Hospital, Harbin Medical UniversityHarbin, China; Department of Physiology, Emory University, AtlantaGA, USA.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Qian
authors.affiliation: Cardiovascular Center, The Fourth Affiliated Hospital, Harbin Medical University Harbin, China.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Li
authors.affiliation: Heart Research and Outcomes Center, Children's Healthcare of Atlanta and Department of Pediatrics, Emory University School of Medicine, Atlanta GA, USA.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Wagner
authors.affiliation: Department of Physiology, Emory University, Atlanta GA, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Chen
authors.affiliation: Cardiovascular Center, The Fourth Affiliated Hospital, Harbin Medical University Harbin, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Song
keywords: adrenergic receptor; cardiac fibrosis; collagen; protein kinase C