Editors choice: Age-Associated Proinflammatory Secretory Phenotype in Vascular Smooth MuscleCells From the Non-human Primate Macaca mulatta: Reversal by ResveratrolTreatment

摘要

There is increasing evidence that age-associated chronic low-grade inflammation promotes the development of both large-vessel disease (myocardial infarction, stroke, peripheral arterial disease) and small-vessel pathologies (including vascular cognitive impairment) in older persons. However, the source of age-related chronic vascular inflammation remains unclear. To test the hypothesis that cell-autonomous mechanisms contribute to the proinflammatory changes in vascular phenotype that accompanies advancing age, we analyzed the cytokine secretion profile of primary vascular smooth muscle cells (VSMCs) derived from young (∼13 years old) and aged (∼21 years old) Macaca mulatta. Aged VSMCs cultured in the absence of systemic factors exhibited significantly increased secretion of interleukin-1β, MCP-1, and tumor necrosis factorα compared with young control cells. Secretion of interleukin-6 also tended to increase in aged VSMCs. This age-associated proinflammatory shift in the cellular secretory phenotype was associated with an increased mitochondrial O2 ⁻ production and nuclear factor κ-light-chain-enhancer of activated B cells activation. Treatment of aged VSMCs with a physiologically relevant concentration of resveratrol (1 μM) exerted significant anti-inflammatory effects, reversing aging-induced alterations in the cellular cytokine secretion profile and inhibitingnuclear factor κ-light-chain-enhancer of activated B cells. Resveratrol alsoattenuated mitochondrial O2⁻ production and upregulated the transcriptional activity of Nrf2 in agedVSMCs. Thus, in non-human primates, cell-autonomous activation of nuclear factorκ-light-chain-enhancer of activated B cells and expression of an inflammatorysecretome likely contribute to vascular inflammation in aging. Resveratrol treatmentprevents the proinflammatory properties of the aged VSMC secretome, an effect that likelycontributes to the demonstrated vasoprotective action of resveratrol in animal models ofaging.