Simvastatin ameliorates senescence-induced mitochondrial dysfunction in vascular smooth muscle cells

Abstract

Background and aims: Senescence and mitochondrial dysfunction are two major indicators of aging. Mitochondria are potential drivers of aging phenotypes and dysfunctional mitochondria are associated with several age-related diseases. There is evidence that senescence induces changes in mitochondrial structure, dynamics, and function. Moreover, senescent vascular smooth muscle cells (VSMCs) are present in atherosclerotic plaques and contribute to their instability. The anti-atherosclerotic effects of simvastatin are well known, but recently other benefits, such as promoting mitochondrial quality and senostatic effects, have been hypothesized. We aimed to analyze simvastatin's senostatic effects in senescent VSMCs.

Methods: We established and characterized mitochondrial dysfunction in doxorubicin-induced senescent VSMCs (doxorubicin) or VSMCs serially passaged to induce replicative senescence (old).

Results: We observed in both senescent models few typical senescence markers such as altered cell morphology, cell cycle inhibitors, laminB1, an accumulation of dysfunctional mitochondria characterized by reduced mitochondrial membrane potential (MMP) and respiration, accumulation of reactive oxygen species (ROS), and an altered mitochondria morphology. Down-regulation of TFAM and TOM70 expression was observed only in old cells suggesting a reduction of mitochondrial biogenesis. Next, we investigated whether simvastatin could ameliorate age-associated phenotypes in senescent VSMCs. Simvastatin 0.1 μM reduces the senescence-associated secretory phenotype (SASP) and ROS production and improves mitochondrial respiration in doxorubicin and old VSMCs. Interestingly, the effects of simvastatin on mitochondrial respiration and SASP were replicated by using a siRNA for the hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, and abolished by adding mevalonic acid, suggesting that these effects are mediated through the inhibition of HMG-CoA reductase.

Conclusions: Our results suggest that simvastatin controls SASP and exerts potentially beneficial therapeutic effects by ameliorating senescence-induced mitochondrial dysfunction in senescent VSMCs.

Keywords: Aging; Mitochondrial dysfunction; Senescence; Statins; Vascular smooth muscle cells.