The usefulness of angiotensin-(1-7) and des-Arg9-bradykinin as novel biomarkers for metabolic syndrome.
The usefulness of angiotensin-(1-7) and des-Arg9-bradykinin as novel biomarkers for metabolic syndrome.
复制标题
血管紧张素-(1-7) 和 des-Arg9-缓激肽作为代谢综合征的新型生物标志物的用途。
DOI：
10.1038/s41440-021-00671-9
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Yokoyama A.
中科院分区：
文献类型：
--
作者：
Sugawara A;Shimada H;Otsubo Y;Kouketsu T;Suzuki S;Yokoyama A.
肾素-血管紧张素系统（RAS）和激肽释放酶-激肽系统（KKS）彼此密切相互作用[1，2]（图1）。在RAS中，血管紧张素原被肾素切割产生血管紧张素I，其随后被血管紧张素转换酶（ACE）切割形成血管紧张素II。然后血管紧张素II与血管紧张素II 1型（AT 1）受体结合，导致诱导血管收缩、炎症、凋亡、肥大、细胞增殖、纤维化和氧化应激[3]。另一方面，通过ACE 2切割血管紧张素II、脑啡肽酶（NEP）切割血管紧张素I或ACE/NEP切割血管紧张素-（1-9）产生的血管紧张素-（1-7）与Mas受体结合并诱导血管舒张、抗炎、抗重塑、抗肥大、抗增殖、抗凋亡和抗氧化作用[3，4]。最近，据报道，口服血管紧张素-（1-7）可预防高脂饮食大鼠的肥胖和肝脏炎症[5]。在KKS中，激肽释放酶从激肽原形成缓激肽（BK）[1，2]，BK与激肽B2受体结合并诱导血管舒张、一氧化氮释放、低血压、抗肥大和抗缺血作用[6，7]。此外，在自发性高血压大鼠中，BK诱导的血管舒张已被血管紧张素-（1-7）增强[8]。BK被ACE（也称为激肽酶II）通过降解成无活性片段而灭活[2]。另一方面，羧肽酶N（也称为激肽酶I）将BK代谢为des-Arg 9-BK [2，6]。Des-Arg 9-BK与激肽B1受体结合并诱导血管收缩、细胞增殖和胶原合成[6，7]，最近Fernandes等人证明，在青少年中，血管紧张素-（1-7）和BK与体重指数（BMI）呈负相关，而血管紧张素I和des-Arg 9-BK与BMI呈正相关，尽管血管紧张素II未显示任何相关性[9]。此外，虽然血管紧张素-（1-7）和BK与稳态模型评估、收缩压和C反应蛋白呈负相关，但血管紧张素I和des-Arg 9-BK与这些参数呈正相关[9]。此外，尽管血管紧张素-（1-7）与甘油三酯呈负相关，但血管紧张素I和des-Arg 9-BK与甘油三酯呈正相关[9]。有趣的是，瘦素与血管紧张素-（1-7）呈负相关，与血管紧张素I和des-Arg 9-BK呈正相关，而脂联素与BK呈正相关[9]。基于这些数据，作者得出结论，血管紧张素-（1-7）和des-Arg 9-BK可能是青少年肥胖的生物学标志物和未来的治疗靶点[9]。在脂肪组织中，所有RAS组分（包括血管紧张素原、ACE和ACE 2）均局部表达，血管紧张素I、血管紧张素II和血管紧张素-（1-7）原位产生[10，11]。有趣的是，用高脂饮食处理的脂肪细胞特异性ACE 2敲除雌性小鼠表现出增强的肥胖诱导的高血压，其与血浆血管紧张素-（1-7）/血管紧张素II比率呈负相关[12，13]。尽管对照组和肥胖患者之间内脏脂肪组织中的ACE 2表达水平没有变化[14]，但小鼠实验表明，长期暴露于高脂饮食诱导脂肪组织中的ADAM 17表达，导致ACE 2从脂肪细胞的细胞膜脱落[15]。因此，我们假设代谢综合征患者脂肪细胞中的ACE 2活性可能会随着病情的持续而逐渐降低，这可能会导致血管紧张素-（1-7）降低和des-Arg 9-BK水平升高（图1.
The renin–angiotensin system (RAS) and the kallikrein–kinin system (KKS) closely interact with each other [1, 2](Fig. 1). In the RAS, angiotensinogen cleavage by renin generates angiotensin I, which is thereafter cleaved by angiotensin-converting enzyme (ACE) to form angiotensin II. Angiotensin II then binds to the angiotensin II type 1 (AT1) receptor, resulting in the induction of vasoconstriction, inflammation, apoptosis, hypertrophy, cell proliferation, fibrosis, and oxidative stress [3]. On the other hand, angiotensin-(1-7), which is generated by the cleavage of angiotensin II by ACE2, by the cleavage of angiotensin I by neprilysin (NEP), or by the cleavage of angiotensin-(1-9) by ACE/NEP, binds to the Mas receptor and induces vasodilatation, antiinflammation, antiremodeling, antihypertrophy, antiproliferation, antiapoptosis, and antioxidation effects [3, 4]. Recently, oral administration of angiotensin-(1-7) has been reported to prevent obesity and hepatic inflammation in rats fed a high-fat diet [5]. In the KKS, kallikrein forms bradykinin (BK) from kininogen [1, 2], and BK binds to the kinin B2 receptor and induces vasodilation, nitric oxide release, hypotension, antihypertrophy, and antiischemic effects [6, 7]. Moreover, BK-induced vasodilation has been shown to be augmented by angiotensin-(1-7) in spontaneously hypertensive rats [8]. BK is inactivated by ACE (also known as kininase II) via degradation into inactive fragments [2]. On the other hand, carboxypeptidase N (also known as kininase I) metabolizes BK into des-Arg9-BK [2, 6]. Des-Arg9-BK binds to the kinin B1 receptor and induces vasocontraction, cell proliferation, and collagen synthesis [6, 7].Recently, Fernandes et al. demonstrated that angiotensin-(1-7) and BK were inversely correlated with body mass index (BMI), while angiotensin I and des-Arg9-BK were positively correlated with BMI in adolescents, although angiotensin II did not show any correlation [9]. Moreover, while angiotensin-(1-7) and BK were inversely correlated with homeostasis model assessment, systolic blood pressure, and C-reactive protein, angiotensin I and des-Arg9-BK were positively correlated with these parameters [9]. Additionally, although angiotensin-(1-7) was inversely correlated with triglycerides, angiotensin I and des-Arg9-BK were positively correlated with them [9]. Interestingly, while leptin inversely was correlated with angiotensin-(1-7) and positively correlated with angiotensin I and des-Arg9-BK, adiponectin was positively correlated with BK [9]. Based on these data, the authors concluded that angiotensin-(1-7) and des-Arg9-BK may possibly be biological markers for adolescent obesity and therapeutic targets in the future [9]. In adipose tissues, all RAS components, including angiotensinogen, ACE, and ACE2, are locally expressed, and angiotensin I, angiotensin II, and angiotensin-(1-7) are produced in situ [10, 11]. Interestingly, adipocyte-specific ACE2 knockout female mice treated with a high-fat diet exhibited augmented obesity-induced hypertension, which was inversely correlated with the plasma angiotensin-(1-7)/angiotensin II ratio [12, 13]. Although ACE2 expression levels in visceral adipose tissues did not vary between control and obese patients [14], mouse experiments demonstrated that chronic exposure to a high-fat diet induced ADAM17 expression in adipose tissue, resulting in the shedding of ACE2 from the cell membrane of adipocytes [15]. We therefore hypothesize that the ACE2 activity in the adipocytes of metabolic syndrome patients may gradually decrease according to the duration of the condition, which may result in the reduction in angiotensin-(1-7) and the increase in des-Arg9-BK levels (Fig. 1 …