血管老化與發炎是導致心血管疾病發展與進程的主要因子。越來越多證據指出細胞老化參與在個體老化與老化相關的疾病，其中包含動脈粥狀硬化與心臟肥大。介白素-1β(Interleukin-1β，IL-1β)為一種促進發炎的細胞激素，在心血管疾病的發生與復發中扮演著重要的角色。我們實驗室先前的研究發現，IL-1β會透過活性氧分子(reactive oxygen species)的生成來誘導血管平滑肌細胞的老化。而最近的一份報告指出，在男性顯著多於女性的川崎氏症病人中，IL-1β在其血管炎的性別差異扮演主要的角色。本研究的目的在探討IL-1β所誘導的胸主動脈血管平滑肌細胞(TA-VSMCs)老化是否存在性別所造成的差異以及其潛在機制。我們以兩種細胞老化的指標蛋白，p16和p21，來偵測源自於雄性與雌性大鼠TA-VSMCs的老化。IL-1β能誘導p16和p21的表現，在雄性TA-VSMCs中以0.1和1 ng/mL的劑量效果最顯著，而雌性TA-VSMCs則以1和10 ng/mL為顯著。我們進一步探討IL-1β受體訊號傳導分子的蛋白表現量在雄性與雌性TA-VSMCs中是否有所不同。在雄性TA-VSMCs中，以1 ng/mL IL-1β處理，IL-1第一型受體（IL-1R1）表現顯著上升，而雌性TA-VSMCs中則沒有顯著變化。另外，IL-1受體拮抗劑(IL-1RA)的表現不論在雄性或雌性TA-VSMCs中皆不受影響。IL-1β誘導的去氧核醣核酸損傷在雄性和雌性TA-VSMCs中皆能透過組蛋白H2A.X的第139位點的絲氨酸磷酸化(ƳH2AX)被偵測到。同樣地，以0.1和1 ng/mL IL-1β處理雄性TA-VSMCs，及以1和10 ng/mL IL-1β處理雌性TA-VSMCs，皆能透過二氫乙啶(dihydroethidium)偵測到細胞內的活性氧分子含量上升。在血管平滑肌細胞中，NADPH氧化酶1（NOX1）和NOX4為生成活性氧分子的主要酵素，因此我們也偵測IL-1β對其表現量的影響。以10 ng/mL IL-1β處理雄性TA-VSMCs，NOX4的表現量上升，但在雌性TA-VSMCs中則無顯著變化。另外，在雄性與雌性TA-VSMCs中，IL-1β對NOX1的表現量皆無影響。總結上述的結果，IL-1β所誘導的大鼠TA-VSMCs的細胞老化可能有輕微的性別差異。IL-1β對IL-1R1與NOX4表現量的刺激作用只在公鼠的血管平滑肌細胞中偵測到，但其角色有待進一步探討。

Vascular aging and inflammation are major contributors to the development and progression of cardiovascular disease. Emerging evidence shows that cellular senescence participates in aging and age-associated diseases, including atherosclerosis and cardiac hypertrophy. Interleukin-1β (IL-1β), a pro-inflammatory cytokine, plays a vital role in occurrence of cardiovascular events and relapses of cardiovascular diseases in human. Previous studies in our laboratory showed that IL-1β induces cellular senescence of vascular smooth muscle cells (VSMCs) in a reactive oxygen species (ROS)-dependent manner. A recent report indicates that IL-1β plays a central role in sex-based differences of vasculitis in Kawasaki disease, which is more prevalent in males than females. This study aimed to determine whether IL-1β-induced cellular senescence of VSMCs displays gender difference and the underlying mechanisms. Cellular senescence was assessed with the expression of two biomarkers, p16 and p21, in VSMCs derived from thoracic aortas (TA-VSMCs) of male and female rats. IL-1β-induced up-regulation of p16 and p21 was most prominent at concentrations of 0.1 and 1 ng/mL in male TA-VSMCs and of 1 and 10 ng/mL in female TA-VSMCs. We next examined whether IL-1β receptor signaling molecules differ in male and female TA-VSMCs. The expression of IL-1 receptor type I (IL-1R1) was up-regulated with IL-1β at 1 ng/mL in male TA-VSMCs, but not in female TA-VSMCs. In contrast, the expression of IL-1 receptor antagonist (IL-1RA) was not affected. Treatment with IL-1β induced DNA damage detected with Ser139 phosphorylation of histone H2A.X (ϒH2AX) in both male and female TA-VSMCs. Similarly, cellular ROS levels assessed with dihydroethidium increased at 0.1 and 1 ng/mL IL-1β in male TA-VSMCs and at 1 and 10 ng/mL IL-1β in female TA-VSMCs. Because NADPH oxidase (NOX) 1 and NOX4 are major enzymes catalyzing ROS production in VSMCs, we examined whether IL-1β differentially affects their expression. The expression of NOX4 was up-regulated in male TA-VSMCs treated with 10 ng/mL IL-1β, but no effect was detected in female TA-VSMCs. In addition, no effect on NOX1 expression was detected in both male and female TA-VSMCs. In summary, an apparent gender difference was detected in IL-1β-induced cellular senescence of TA-VSMCs derived from male and female rats. IL-1β up-regulates IL-1R1 and NOX4 in male but not female TA-VSMCs, and potential roles need further investigation.

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