Matrix metalloproteinase-2 and-9 exacerbate arterial stiffening and angiogenesis in diabetes and chronic kidney disease
Matrix metalloproteinase-2 and-9 exacerbate arterial stiffening and angiogenesis in diabetes and chronic kidney disease
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DOI：
10.1093/cvr/cvp242
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发表时间：
2009-12-01
影响因子：
10.8
通讯作者：
Levin, Adeera
中科院分区：
文献类型：
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作者：
Chung, Ada W. Y.;Yang, H. H. Clarice;Levin, Adeera
慢性肾脏病（CKD）和糖尿病是心血管疾病（CVD）的主要危险因素。基质金属蛋白酶（MMP-2和MMP-9）通过降解弹性纤维调节血管结构，通过产生血管抑素抑制血管新生。我们假设MMP-2和MMP-9在CKD合并糖尿病患者的动脉血管中表达上调，与那些没有糖尿病的患者相比，在活体供体移植过程中，从供体（n = 8）和受体（非糖尿病，n = 8;糖尿病，n = 8;年龄，性别和透析治疗匹配）收集动脉。与非糖尿病动脉相比，糖尿病动脉的MMP-2和MMP-9活性分别增加了42%和116%。糖尿病动脉硬化程度最高，且硬化程度与MMP-2 + MMP-9活性之和高度相关（r = 0.738，P = 0.0002）。脉搏波传导速度与MMP活性相关（r = 0.683，P = 0.005）。糖尿病血管弹性纤维降解和钙化最严重。糖尿病患者的磷酸盐水平高出25%，分别与MMP活性（r = 0.513，P = 0.04）和体外硬度（r = 0.545，P = 0.03）相关。与非糖尿病血管相比，糖尿病血管中血管生长抑制素的表达增加了一倍，而血管内皮生长因子减少了50%。糖尿病血管微血管密度为非糖尿病血管的48%，且与MMP活性密切相关（r =-0.792，P < 0.0001）和血管舒张（r = 0.685，P = 0.0009）。采用配对病例对照设计，我们报道了糖尿病CKD动脉中MMP-2和MMP-9的上调，并与硬化相关，血管生成受损和内皮功能障碍。这些发现可能有助于解释糖尿病和非糖尿病CKD患者对CVD的高易感性。
Chronic kidney disease (CKD) and diabetes are the prominent risk factors of cardiovascular disease (CVD). Matrix metalloproteinase (MMP)-2 and -9 regulate vascular structure by degrading elastic fibre and inhibit angiogenesis by generating angiostatin. We hypothesized that MMP-2 and -9 were up-regulated in the arterial vasculature from CKD patients with diabetes, compared with those without diabetes.During living donor transplantation procedures, arteries from donors (n = 8) and recipients (non-diabetic, n = 8; diabetic, n = 8; matched in age, gender, and dialysis treatments) were harvested. Diabetic arteries had increased MMP-2 and -9 activities by 42 and 116% compared with non-diabetic ones. Diabetic arteries were the stiffest, and the stiffness measurement was highly correlated with the summation of MMP-2 + MMP-9 activities (r = 0.738, P = 0.0002). Pulse wave velocity measurements correlated with MMP activity (r = 0.683, P = 0.005). Elastic fibre degradation and calcification were worst in diabetic vessels. The phosphate level, which was 25% higher in diabetic patients, correlated with MMP activity (r = 0.513, P = 0.04) and in vitro stiffness (r = 0.545, P = 0.03), respectively. Angiostatin expression was doubled, whereas vascular endothelial growth factor was 50% reduced in diabetic compared with non-diabetic vessels. Microvascular density in diabetic vessels was 48% of that in non-diabetic ones, and it was strongly associated with MMP activity (r = -0.792, P < 0.0001) and vasorelaxation (r = 0.685, P = 0.0009).Using a matched case-control design, we report up-regulation of MMP-2 and -9 in diabetic CKD arteries and correlate those with stiffening, impaired angiogenesis, and endothelial dysfunction. These findings may help to explain the high susceptibility of CVD in diabetic and non-diabetic CKD patients.