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

Abstract

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-α and galectin-3 in the development of HF. We found that activation of PKC by phorbol dibutyrate (PDB) increased galectin-3 expression by ~180%, as well as collagen I and 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 β-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 ~140% in the right ventricle and also by ~240% in left ventricle compared to control. The elevated galectin-3 is consistent with an increase of total and activated (phosphorylated) PKC-α, α-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-α pathway and increased galectin-3 expression and collagen production. This study provides a new insight into the molecular mechanisms of HF mediated by PKC-α and galectin-3. PKC-α promotes cardiac fibrosis and HF by stimulation of galectin-3 expression.

Biomarkers in patients with myocardial fibrosis

“…Galectin-3 expression could be increased by PKC activation, which leads to collagen I and fibronection accumulation in cardiomyocytes. The regulation of collagen production indicates that galectin-3 can mediate PKC-induced cardiac fibrosis in heart failure [29].…”

Activation of TGF-β1/α-SMA/Col I Profibrotic Pathway in Fibroblasts by Galectin-3 Contributes to Atrial Fibrosis in Experimental Models and Patients

“…Consistent with this result, we found that the TGF-β1/α-SMA/Col I pathway was induced in neonatal rat cardiac fibroblasts by Gal-3-enriched conditioned HL-1 culture media, and further confirmed the role of Gal-3 in fibroblast differentiation and proliferation with recombinant human Gal-3 protein treatment, both at 10 and 30 μg/mL; exogenous Gal-3 activated the profibrotic pathway and induced fibroblast proliferation, as detected by CCK-8. All of these results led us to the conclusion that although cardiomyocytes barely express Gal-3 under physiological conditions [9], under pathological conditions, cardiomyocytes may also act as an alternative source of Gal-3 [23,24], inducing fibroblasts to synthesize collagen and other pro-fibrotic components of the extracellular matrix.…”

“…However, some also reported that Gal-3 is expressed in ventricular myocytes in a pressure-overloaded remodeling heart model and that a high density of Gal-3-positive myocytes is related to abnormalities in remodeling and heart function [23]. Furthermore, HL-1 cells have been demonstrated to express Gal-3 at baseline and remarkably induce its expression following protein kinase C activation, indicating that cardiomyocytes may also act as a source of Gal-3 in the heart [24] and possibly be greatly induced in pathological conditions. Moreover, it has long been verified that rapidly-paced cardiomyocytes release substances that profoundly alter cardiac fibroblast function, although without identification of candidate molecules contributing to this effect [25].…”

Involvement of the Renin‐Angiotensin System in Atherosclerosis

“…Significant upregulation of MMP-8 gene expression in carotid plaque tissue was observed in patients carrying haplotype G(-381)T(-799) of two MMP-8 promoter polymorphisms rs11225395 (-799 C/T) and rs1320632 (-381 A/G) [82]. Recently, it was shown that Ang II treatment in vitro causes increased collagen I synthesis and galectin-3 (Gal-3) expression in mouse HL-1 cardiomyocytes via protein kinase Calpha (PKC-α) pathway [83]. Gal-3 is involved in all processes active in atherosclerosis: cell adhesion, cell activation and chemoattraction, cell growth and differentiation [84].…”