Laboratory of Cardiovascular Science, Intramural Research Program, 5600 Nathan Shock Dr, National Institute on Aging-National Institutes of Health, Baltimore, MD 21030, USA.
Hypertension. 2012 Aug;60(2):459-66. doi: 10.1161/HYPERTENSIONAHA.112.191270. Epub 2012 Jun 11.
Age-associated arterial remodeling involves arterial wall collagen deposition and elastin fragmentation, as well as an increase in arterial pressure. This arterial remodeling is linked to proinflammatory signaling, including transforming growth factor-β1, monocyte chemoattractant protein 1, and proendothelin 1, activated by extracellular matrix metalloproteinases (MMPs) and orchestrated, in part, by the transcriptional factor ets-1. We tested the hypothesis that inhibition of MMP activation can decelerate the age-associated arterial proinflammation and its attendant increase in arterial pressure. Indeed, chronic administration of a broad-spectrum MMP inhibitor, PD166739, via a daily gavage, to 16-month-old rats for 8 months markedly blunted the expected age-associated increases in arterial pressure. This was accompanied by the following: (1) inhibition of the age-associated increases in aortic gelatinase and interstitial collagenase activity in situ; (2) preservation of the elastic fiber network integrity; (3) a reduction of collagen deposition; (4) a reduction of monocyte chemoattractant protein 1 and transforming growth factor-β1 activation; (5) a diminution in the activity of the profibrogenic signaling molecule SMAD-2/3 phosphorylation; (6) inhibition of proendothelin 1 activation; and (7) downregulation of expression of ets-1. Acute exposure of cultured vascular smooth muscle cells in vitro to proendothelin 1 increased both the transcription and translation of ets-1, and these effects were markedly reduced by MMP inhibition. Furthermore, infection of vascular smooth muscle cells with an adenovirus harboring a full-length ets-1 cDNA increased activities of both transforming growth factor-β1 and monocyte chemoattractant protein 1. Collectively, our results indicate that MMP inhibition retards age-associated arterial proinflammatory signaling, and this is accompanied by preservation of intact elastin fibers, a reduction in collagen, and blunting of an age-associated increase in blood pressure.
年龄相关的动脉重塑涉及动脉壁胶原蛋白沉积和弹性蛋白碎片化，以及动脉压升高。这种动脉重塑与促炎信号有关，包括转化生长因子-β1、单核细胞趋化蛋白 1 和原内皮素 1，这些信号由细胞外基质金属蛋白酶 (MMPs) 激活，并部分由转录因子 ets-1 协调。我们测试了抑制 MMP 激活是否可以减缓与年龄相关的动脉炎症及其伴随的动脉压升高的假说。事实上，通过每日灌胃，给 16 个月大的大鼠连续 8 个月给予广谱 MMP 抑制剂 PD166739，可显著减弱预期的与年龄相关的动脉压升高。这伴随着以下变化：(1) 抑制主动脉明胶酶和间质胶原酶活性的年龄相关性增加；(2) 保持弹性纤维网络完整性；(3) 减少胶原蛋白沉积；(4) 减少单核细胞趋化蛋白 1 和转化生长因子-β1 的激活；(5) 减少促纤维生成信号分子 SMAD-2/3 磷酸化的活性；(6) 抑制原内皮素 1 的激活；(7) 下调 ets-1 的表达。体外培养的血管平滑肌细胞急性暴露于内皮素 1 可增加 ets-1 的转录和翻译，而 MMP 抑制可显著降低这些作用。此外，用含有全长 ets-1 cDNA 的腺病毒感染血管平滑肌细胞，可增加转化生长因子-β1 和单核细胞趋化蛋白 1 的活性。总的来说，我们的结果表明，MMP 抑制可减缓与年龄相关的动脉促炎信号，同时保持完整的弹性纤维，减少胶原蛋白，并减弱与年龄相关的血压升高。
