Protein kinase C promotes cardiac fibrosis and heart failure by modulating galectin-3 expression

Protein kinase C (PKC) and galectin-3 are two important mediators that play a key pathogenic role in cardiac hypertrophy and heart failure (HF). However, the molecular mechanisms and signaling pathways are not fully understood. In this study, we explored the relationship between and roles of PKC-alpha and galectin-3 in the development of HF. We found that activation of PKC by phorbol dibutyrate (PDB) increased galectin-3 expression by similar to 180%, as well as collagen land fibronection accumulation in cultured HL-1 cardiomyocytes. Over-expression of galectin-3 in HL-1 cells increased collagen I protein production. Inhibition of galectin-3 by beta-lactose blocked PDB-induced galectin-3 and collagen production, indicating that galectin-3 mediates PKC-induced cardiac fibrosis. In rats subjected to pulmonary artery banding (PAB) to induce right ventricular HF, galectin-3 was increased by similar to 140% in the right ventricle and also by similar to 240% in left ventricle compared to control. The elevated galectin-3 is consistent with an increase of total and activated (phosphorylated) PKC-alpha, alpha-SMA and collagen I. Finally, we extended our findings to examine the role of angiotensin II (Ang II), which activates the PKC pathway and contributes to cardiac fibrosis and the development of HF. We found that Ang II activated the PKC-alpha pathway and increased galectin-3 expression and collagen production. This study provides a new insight into the molecular mechanisms of HF mediated by PKC-alpha and galectin-3. PKC-alpha promotes cardiac fibrosis and HF by stimulation of galectin-3 expression. (C)2014 Elsevier B.V. All rights reserved.