Modulation of angiotensin II-mediated hypertension and cardiac remodeling by lectin-like oxidized low-density lipoprotein receptor-1 deletion
Modulation of angiotensin II-mediated hypertension and cardiac remodeling by lectin-like oxidized low-density lipoprotein receptor-1 deletion
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DOI：
10.1161/hypertensionaha.108.115287
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发表时间：
2008-09-01
期刊：
影响因子：
8.3
通讯作者：
Mehta, Jawahar L.
中科院分区：
文献类型：
--
作者：
Hu, Changping;Dandapat, Abhijit;Mehta, Jawahar L.
血管紧张素II通过1型受体激活上调凝集素样氧化低密度脂蛋白受体- 1 （LOX- 1）的表达，而LOX- 1激活又上调血管紧张素II 1型受体的表达。我们假设这种正反馈回路的中断可能会减弱血管紧张素II诱导的高血压和随后的心脏重构的发生。为了验证这一假设，将LOX- 1敲除小鼠和野生型小鼠注入血管紧张素II或去甲肾上腺素（血管紧张素II的对照）4周。在LOX- 1基因敲除小鼠中，血管紧张素II-而非去甲肾上腺素-诱导的高血压减轻。在LOX- 1基因敲除小鼠中，血管紧张素II诱导的心脏重构也被减弱。重要的是，在给予血管紧张素II的LOX- 1敲除小鼠的组织中，血管紧张素II型1受体表达降低，内皮NO合成酶的表达和活性保持不变。在给予血管紧张素II的LOX- 1敲除小鼠中，活性氧的产生、烟酰胺腺嘌呤二核苷酸磷酸氧化酶的表达以及p38和p44/ 42丝裂原活化蛋白激酶的磷酸化也明显减少。这些生化和结构异常的改变与LOX- 1基因敲除小鼠心脏血流动力学的保存有关。为了证实在LOX- 1缺失的情况下成纤维细胞的功能是被调节的，我们用血管紧张素II处理野生型和LOX- 1敲除小鼠的心脏成纤维细胞。事实上，LOX- 1基因敲除小鼠心脏成纤维细胞在血管紧张素II治疗下显示出减弱的纤维化反应。这些观察结果提供了强有力的证据，证明LOX- 1是血管紧张素II诱导的高血压和随后的心脏重构发展的关键调节剂。
Angiotensin II via type 1 receptor activation upregulates the expression of lectin- like oxidized low- density lipoprotein receptor- 1 (LOX- 1), and LOX- 1 activation, in turn, upregulates angiotensin II type 1 receptor expression. We postulated that interruption of this positive feedback loop might attenuate the genesis of angiotensin II- induced hypertension and subsequent cardiac remodeling. To examine this postulate, LOX- 1 knockout and wild- type mice were infused with angiotensin II or norepinephrine (control for angiotensin II) for 4 weeks. Angiotensin II-, but not norepinephrine-, induced hypertension was attenuated in LOX- 1 knockout mice. Angiotensin II- induced cardiac remodeling was also attenuated in LOX- 1 knockout mice. Importantly, angiotensin II type 1 receptor expression was reduced, and the expression and activity of endothelial NO synthase were preserved in the tissues of LOX- 1 knockout mice given angiotensin II. Reactive oxygen species generation, nicotinamide- adenine dinucleotide phosphate oxidase expression, and phosphorylation of p38 and p44/ 42 mitogen- activated protein kinases were also much less pronounced in the LOX- 1 knockout mice given angiotensin II. These alterations in biochemical and structural abnormalities were associated with preservation of cardiac hemodynamics in the LOX- 1 knockout mice. To confirm that fibroblast function is modulated in the absence of LOX- 1, cardiac fibroblasts from wild- type and LOX- 1 knockout mice were treated with angiotensin II. Indeed, LOX- 1 knockout mice cardiac fibroblasts revealed an attenuated profibrotic response on treatment with angiotensin II. These observations provide strong evidence that LOX- 1 is a key modulator of the development of angiotensin II- induced hypertension and subsequent cardiac remodeling.