Title

Statin therapy reduces differentiation of ventricular fibroblast to myofibroblasts in human failing heart

Aurora Affiliations

Sheikh Khalifa Bin-Hamad Al-Thani Center for Integrative Research on Cardiovascular Aging, Aurora Research Institute, Aurora Health Care

Abstract

Background Cardiac fibrosis (CF) is a major factor underlying the progression of heart failure (HF). Apart from the established lipid lowering effect, HMG-CoA (3-hydroxy-3-methylglutaryl-CoenzymeA) reductase inhibition by statins reverses CF in various animal models of HF but its effect in human failing heart ventricular fibroblasts (hVF), responsible for fibrosis, is not known. Hence, we tested the differentiation phenotype of hVF isolated from HF patients under statin therapy (HF+Statin) for at least 1 year or not (HF-No_Statin) and normal, as fibroblast to myofibroblast trans-differentiation precedes fibrosis.

Methods Primary hVF cultures obtained from HF patients undergoing left-ventricle assist device implantation (n=4 each) and non-diseased hVF from trauma victims (n=3) were used at passage 3 or 4. Confocal microscopy, immunohistochemistry, western blotting, Edu (5-ethynyl-2′-deoxyuridine)-incorporation assay data were obtained and analyzed by unpaired t test or one-Way Analysis of Variance.

Results Immunoblot (Fig. A) data showed significantly (P+) and immunohistochemistry (Fig. B) showed significantly high population of myofibroblasts (α-SMA+) in the HF-No_Statin group vs the control or HF+Statin groups, suggesting statin-sensitive increased hVF differentiation in failing heart. In vitrotreatment of simvastatin (0.3μM for 72 hrs) on HF-No_Statin group hVFs significantly (P

Conclusion The failing heart ventricle has a large population of differentiated myofibroblasts. Statins prevent/reverse hVF differentiation decreasing the ratio of myofibroblast to fibroblasts, which is anti-fibrotic. The significance of statins’ anti-fibrotic effect for HF therapeutics may be in reducing the CF progression by inhibiting/reversing hVF differentiation to myofibroblasts, thereby improving the cardiovascular outcome in HF patients

Support or Funding Information

Aurora Health Care - Cardiovascular Surgery Research Award (CVSRA 2015) to Gracious R Ross and NIH R01-HL101240 to Arshad Jahangir.

Document Type

Abstract

DOI

10.1096/fj.1530-6860