A time course investigation of the statin paradox among valvular interstitial cell phenotypes

Statin drugs are prescribed primarily for their ability to lower cholesterol, but may also exert beneficial side effects unrelated to cholesterol metabolism. Previous work has described a "statin paradox," where statin treatment decreased osteoblastic markers in valve myofibroblasts while increasing those same markers in preosteoblasts. However, valvular interstitial cells (VICs) themselves are a multipotent cell type, capable of differentiating into activated, myofibroblastic VICs (aVICs) and osteoblastic VICs (obVICs), motivating the question of whether the statin paradox can exist within an individual valve containing these phenotypically distinct VIC subpopulations. In the current study, a heterogeneous initial population of porcine VICs was differentiated into aVICs or obVICs and treated with simvastatin. Gene expression analysis was conducted daily over an 8-day time course to capture temporally dynamic changes in cell phenotype induced by statin treatment. These studies demonstrated that the two VIC populations, aVICs and obVICs, exhibited differential responses to statin treatment. Specifically, simvastatin increased the expression of osteoblastic markers in obVICs, but not in aVICs, while also suppressing the myofibroblastic phenotype in both aVICs and obVICs. These results indicate that the statin paradox can exist within the heterogeneous VIC population of an individual diseased valve and that statin efficacy in the context of calcific aortic valve disease (CAVD) may be dependent upon the cellular composition of the valve. These findings may have implications for clinical usage of statins, shedding light on how statin efficacy in CAVD may be dependent upon the disease stage or why some individuals exhibit better responsiveness to statin therapy.