Metalloproteinases damage the insulin receptor to cause insulin resistance in spontaneously hypertensive rats.
Metalloproteinases damage the insulin receptor to cause insulin resistance in spontaneously hypertensive rats.
复制标题
金属蛋白酶损伤胰岛素受体，导致自发性高血压大鼠胰岛素抵抗。
DOI：
10.1161/hypertensionaha.107.108902
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Bohlen,HGlenn
中科院分区：
文献类型：
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作者：
Bohlen,HGlenn
Delano和Schmid-Schönbein 1的研究指出，在自发性高血压大鼠（SHR）中，胰岛素抵抗机制与高血压可能存在非常重要的重叠。他们的研究可能对肥胖和高血压人群都很重要。随着国家和国际上对肥胖及其伴随的心血管问题的重视，人们往往忘记原发性高血压与严重肥胖影响相同比例的人，甚至比2型糖尿病影响更高比例的人。肥胖导致胰岛素抵抗，在严重的情况下，2型糖尿病，确实有一种遗传倾向，病人的生活方式可以减轻。然而，即使在瘦人群中，高血压也有既定的遗传基础，尽管尽一切努力避免不适当的生活方式问题，但仍经常发生。肥胖和高血压的遗传人群明显重叠，并且可能共享一些机制，导致许多常见的血管和心脏病变。1988年，Horl等人的一项研究注意到SHR中存在胰岛素抵抗。2当时，这似乎很不寻常，因为SHR通常很瘦，胰岛素抵抗依赖于一定程度的肥胖是一个普遍的概念。1991年，Reaven和Chang 3和Reaven 4质疑在SHR和高血压人群中胰岛素抵抗是否导致高血压或反之亦然。自1988年以来，人们对高血压和胰岛素抵抗的兴趣已经产生了200篇文章，涉及SHR中胰岛素抵抗的各种问题，大约有5000篇关于人类和动物胰岛素抵抗和血压异常的文章。我们在临床和基础科学领域对这个问题已经非常了解，以至于我们共同认为胰岛素抵抗和某种程度的高血压是一种预期的关系。我们经常问的是，这些异常中哪一个先发生。Delano和Schmid-Schönbein 1的研究部分解决了这个问题，因为动脉压升高可能是基质降解金属蛋白酶（基质金属蛋白酶[MMP]-9）激活的第一步，而基质降解金属蛋白酶在胰岛素抵抗级联反应中似乎非常重要。该图呈现了导致与增加的氧自由基产生和金属蛋白酶释放相关的炎症状态的高血压的假设示意图。高血压导致这种状态的假设被强调为一个问号，因为这个过程中的联系既复杂又可能是相互作用的。5例如，高血压中氧自由基的来源可能始于NADPH氧化酶活性的增加，但随着内皮细胞受损，进展为内皮NO合酶的解偶联。6在任一种或两种情况下，氧自由基可以作为血管肌肉的血管收缩剂和内皮细胞的损伤剂，以限制NO和其他内皮依赖性血管扩张剂。然而，现在看来，氧自由基问题只是导致血管阻力升高的方案的一部分。从Delano和Schmid-Schönbein 1的研究中了解到，炎症过程的一部分是MMP-9对细胞表面受体的损伤，这一点尤为重要。虽然这项研究的重点是胰岛素受体，但有理由怀疑许多细胞表面蛋白可能容易受到损伤，从而干扰内皮细胞和血管肌肉细胞功能的调节。这可能会导致一个理解，为什么有.
The elegant study by Delano and Schmid-Schönbein1 points to a potentially very important overlap of an insulin resistance mechanism with hypertension in the spontaneously hypertensive rat (SHR). Their investigation will likely be important to both the obese and hypertensive populations. With the national and international emphasis on obesity and its attendant cardiovascular problems, there is a tendency to forget that essential hypertension affects about the same percentage of humans as does serious obesity and an even higher percentage of the population than does type 2 diabetes mellitus. Obesity leading to insulin resistance and, in severe situations, type 2 diabetes mellitus, does have a genetic predisposition that the patient’s lifestyle can mitigate. However, hypertension even in the lean population has an established genetic basis and often develops despite every attempt to avoid inappropriate lifestyle issues. There is obviously an overlap of the obese and hypertensive genetic populations and likely a sharing of some mechanisms to cause many of their common vascular and cardiac pathologies. The existence of insulin resistance in the SHR came to attention in 1988 by a study by Horl et al. 2 At the time, this seemed rather unusual, because the SHR is generally quite lean, and the dependence of insulin resistance on some degree of obesity was a common concept. In 1991, Reaven and Chang3 and Reaven4 questioned whether the insulin resistance leads to hypertension or vice versa in the SHR and hypertensive humans. The interest in hypertension and insulin resistance since 1988 has generated 200 articles dealing with various issues of insulin resistance in the SHR with something of the order of 5000 articles on insulin resistance and blood pressure abnormalities in humans and animals. We in clinical and basic sciences have been so well informed on this issue that we collectively take insulin resistance and some degree of hypertension as an expected relationship. What we often question is which of these abnormalities occurs first. This question is partially addressed in the study by Delano and Schmid-Schönbein1 in the context that elevated arterial pressure may be the first step in the activation of matrix-degrading metalloproteinases (matrix metalloproteinase [MMP]-9) that appears to be quite important in the cascade to insulin resistance. The Figure presents a hypothetical scheme of hypertension leading to an inflammatory state associated with increased oxygen radical generation and metalloproteinase release. The assumption of hypertension leading to this status is highlighted as a question mark, because the links in this process are both complicated and, likely, interactive. 5 For example, the source of oxygen radicals in hypertension may start with increased NADPH oxidase activity but progress to uncoupling of endothelial NO synthase as endothelial cells are compromised. 6 In either or both scenarios, oxygen radicals can act as vasoconstrictors for vascular muscle and injury agents for endothelial cells to limit NO and other endothelial-dependent vasodilators. However, it now appears that oxygen radical issues are only part of the scheme leading to elevated vascular resistance. It is particularly important to learn from the study by Delano and Schmid-Schönbein1 that part of the inflammatory process is cell surface receptor damage by MMP-9. Although the emphasis of the study is the insulin receptor, it is reasonable to suspect that many cell surface proteins could be vulnerable to damage and, consequently, disturbing regulation of endothelial and vascular muscle cell functions. This may lead to an understanding as to why there …