Department of Cardiology and Emergency, Yanbian University Hospital, Jilin, PR China; Department of Geriatrics, Nagoya University Graduate School of Medicine, Japan.
Department of Cardiology and Emergency, Yanbian University Hospital, Jilin, PR China.
Int J Cardiol. 2018 Sep 15;267:150-155. doi: 10.1016/j.ijcard.2018.05.089. Epub 2018 May 24.
The mechanism by which angiogenesis declines with aging remains largely unknown. Given that the plasma levels of adiponectin (APN) are decreased in the presence of ischemic cardiovascular disease, we explore the possible mechanisms by which APN/adiponectin receptor1 (AdipoR1) axis inactivation contributes to the decline in vascular regeneration capacity in elderly animals.
To study aging-related changes in the APN/AdipoR1 axis and its impact on ischemia-induced angiogenesis, a hindlimb ischemia model was applied to young and aged mice. Aging impaired ischemia-induced blood flow recovery. An ELISA showed that the aged mice had decreased plasma APN levels. Immunostaining showed lesser capillary formation in the aged mice. The aged ischemic muscles had decreased levels of AdipoR1, peroxisome proliferator activated receptor-γ (PPAR-γ), PPAR-γ co-activator 1α (PGC-1α), phospho-AMP-activated protein kinase α (p-AMPK-α), and B cell lymphoma-2 (Bcl-2) and increased levels of cleaved caspase-8 (C-caspase-8) and gp91phox/p22phox genes or/and proteins, nicotinamide adenine dinucleotide phosphate oxidase activity, superoxide production, and matrix metalloproteinase-2/-9 activity as well as increased numbers of infiltrated macrophages and leucocytes. In in vitro experiments, aged endothelial cells had negative changes in the levels of PPAR-γ, PGC-1α, p-AMPK-α, Bcl-2, and C-caspase-8 proteins in response to oxidative stress. Genetic interventions targeted toward APN and AdipoR1 negatively affected the targeted angiogenic protein levels in aged muscles and angiogenic actions and/or aged endothelial events.
These findings indicate that aging can reduce angiogenesis in response to hypoxia via an impaired APN-AdipoR1-dependent mechanism that may be mediated by PPAR-γ/PGC-1α signaling inactivation in advanced age.
血管生成随年龄增长而下降的机制在很大程度上尚不清楚。鉴于在存在缺血性心血管疾病的情况下，脂联素（APN）的血浆水平降低，我们探讨了 APN/脂联素受体 1（AdipoR1）轴失活导致老年动物血管再生能力下降的可能机制。
为了研究与衰老相关的 APN/AdipoR1 轴变化及其对缺血诱导的血管生成的影响，我们将后肢缺血模型应用于年轻和老年小鼠。衰老会损害缺血诱导的血流恢复。ELISA 显示，老年小鼠的血浆 APN 水平降低。免疫染色显示，老年小鼠的毛细血管形成减少。老年缺血肌肉中的 AdipoR1、过氧化物酶体增殖物激活受体-γ（PPAR-γ）、PPAR-γ 共激活剂 1α（PGC-1α）、磷酸化 AMP 激活蛋白激酶 α（p-AMPK-α）和 B 细胞淋巴瘤-2（Bcl-2）水平降低，而 cleaved caspase-8（C-caspase-8）和 gp91phox/p22phox 基因或/和蛋白、烟酰胺腺嘌呤二核苷酸磷酸氧化酶活性、超氧化物产生、基质金属蛋白酶-2/-9 活性以及浸润的巨噬细胞和白细胞数量增加。在体外实验中，衰老的内皮细胞对氧化应激的反应中，PPAR-γ、PGC-1α、p-AMPK-α、Bcl-2 和 C-caspase-8 蛋白的水平发生了负向变化。针对 APN 和 AdipoR1 的基因干预会对衰老肌肉中的靶向血管生成蛋白水平以及血管生成作用和/或衰老内皮事件产生负面影响。
这些发现表明，衰老可以通过一种受损的 APN-AdipoR1 依赖性机制减少对缺氧的血管生成，这种机制可能是由高级年龄中 PPAR-γ/PGC-1α 信号失活介导的。
