Title

Simvastatin inhibits human atrial fibroblast proliferation through cell-cycle regulating cyclins by mevalonic acid-dependent pathway

Aurora Affiliations

Aurora Research Institute

Abstract

Background: Atrial fibrosis contributes to the development and progression of atrial fibrillation (AF), and drugs targeting the fibrosis process may help reduce the burden of AF. Statins are cholesterol-lowering drugs known to reduce AF through the cholesterol-independent pathway, but the underlying anti-fibrotic effects are not fully defined. We sought to determine the effect of simvastatin on the proliferation of human atrial fibroblasts responsible for cardiac fibrosis and define the target proteins involved in cell cycle regulation affected by simvastatin.

Methods: The proliferative capacity of atrial fibroblasts isolated from the right atrial appendages of patients undergoing open heart surgery was quantified in the absence and presence of simvastatin (0-25µM). The rate of fibroblast proliferation (doubling time), DNA synthesis [5-ethynyl-2’-deoxyuridine (EdU) incorporation assay] and cell cycle progression (flow cytometry) was determined along with the expression of message for cyclins A, D and E (RT-PCR) and protein (Cyclin D, Western blot).

Results:Simvastatin decreased the rate of serum-induced atrial fibroblast proliferation by 65%, DNA synthesis by 85% (p

Conclusions: Statins inhibit fibroblast proliferation through down-regulation of cell-cycle regulating cyclin genes through the MVA dependent pathway.

Document Type

Abstract

DOI

10.1016/S0735-1097(16)30671-4