Hypercholesterolemia-induced erectile dysfunction: endothelial nitric oxide synthase (eNOS) uncoupling in the mouse penis by NAD(P)H oxidase.
Hypercholesterolemia-induced erectile dysfunction: endothelial nitric oxide synthase (eNOS) uncoupling in the mouse penis by NAD(P)H oxidase.
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DOI：
10.1111/j.1743-6109.2010.01880.x
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Burnett AL
中科院分区：
文献类型：
--
作者：
Musicki B;Liu T;Lagoda GA;Strong TD;Sezen SF;Johnson JM;Burnett AL
高胆固醇血症主要通过增加氧化应激和损害阴茎内皮功能诱导勃起功能障碍（艾德），但调节阴茎中活性氧（ROS）产生的机制尚不清楚。我们评估了高胆固醇血症是否激活阴茎中的烟酰胺腺嘌呤二核苷酸磷酸（NAD[P]H）氧化酶，提供ROS的初始来源以诱导内皮型一氧化氮合酶（eNOS）解偶联和内皮功能障碍，从而导致ED。低密度脂蛋白受体（LDLR）缺失小鼠饲喂西方饮食4周以诱导早期高脂血症。喂食常规食物的野生型（WT）小鼠作为对照。小鼠接受NAD（P）H氧化酶抑制剂夹竹桃苷（10 mM，在饮用水中）或载体。勃起功能评估海绵体神经电刺激的反应。内皮功能标志物（磷酸[P]-血管舒张刺激蛋白[VASP]-Ser-239）、氧化应激（4-羟基-2-壬烯醛[HNE]）、ROS来源（eNOS解偶联和NAD[P]H氧化酶亚基p67 phox、p47 phox和gp 91 phox）、P-eNOS-Ser-1177和eNOS通过Western印迹法在阴茎中进行测量。高胆固醇血症诱导ED中ROS产生和内皮功能障碍的分子机制。与WT小鼠相比，高胆固醇血症LDLR缺失小鼠的勃起反应显著降低（P<0.05）。与野生型小鼠相比，高胆固醇血症小鼠阴茎中NAD（P）H氧化酶亚基p67 phox、p47 phox和gp 91 phox、eNOS解偶联和4-HNE修饰蛋白的蛋白表达增加（P <0.05），P-VASP-Ser-239的表达减少（P <0.05）。夹竹桃麻素处理的LDLR-敲除小鼠保持了（P<0.05）最大阴茎海绵体内压，并逆转了（P < 0.05）阴茎中gp 67 phox和gp 47 phox、4-HNE、P-VASP-Ser-239和eNOS解偶联蛋白表达的异常。WT小鼠的夹竹桃麻素治疗不影响任何这些参数。P-eNOS-Ser-1177和总eNOS的蛋白表达不受高胆固醇血症的影响。阴茎中激活的NAD（P）H氧化酶是导致eNOS解偶联的氧化应激的最初来源，从而提供了高胆固醇血症诱导的ED中eNOS解偶联和内皮功能障碍的机制。
Hypercholesterolemia induces erectile dysfunction (ED) mostly by increasing oxidative stress and impairing endothelial function in the penis, but the mechanisms regulating reactive oxygen species (ROS) production in the penis are not understood. We evaluated whether hypercholesterolemia activates nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase in the penis, providing an initial source of ROS to induce endothelial nitric oxide synthase (eNOS) uncoupling and endothelial dysfunction resulting in ED. Low-density-lipoprotein receptor (LDLR)–null mice were fed Western diet for 4 weeks to induce early-stage hyperlipidemia. Wild type (WT) mice fed regular chow served as controls. Mice received NAD(P)H oxidase inhibitor apocynin (10 mM in drinking water) or vehicle. Erectile function was assessed in response to cavernous nerve electrical stimulation. Markers of endothelial function (phospho [P]-vasodilator-stimulated-protein [VASP]-Ser-239), oxidative stress (4-hydroxy-2-nonenal [HNE]), sources of ROS (eNOS uncoupling and NAD[P]H oxidase subunits p67phox, p47phox, and gp91phox), P-eNOS-Ser-1177, and eNOS were measured by Western blot in penes. Molecular mechanisms of ROS generation and endothelial dysfunction in hypercholesterolemia-induced ED. Erectile response was significantly (P<0.05) reduced in hypercholesterolemic LDLR-null mice compared to WT mice. Relative to WT mice, hypercholesterolemia increased (P<0.05) protein expressions of NAD(P)H oxidase subunits p67phox, p47phox and gp91phox, eNOS uncoupling, and 4-HNE-modified proteins, and reduced (P<0.05) P-VASP-Ser-239 expression in the penis. Apocynin treatment of LDLR-null mice preserved (P<0.05) maximal intracavernosal pressure, and reversed (P < 0.05) the abnormalities in protein expressions of gp67phox and gp47phox, 4-HNE, P-VASP-Ser-239, and eNOS uncoupling in the penis. Apocynin treatment of WT mice did not affect any of these parameters. Protein expressions of P-eNOS-Ser-1177 and total eNOS were unaffected by hypercholesterolemia. Activated NAD(P)H oxidase in the penis is an initial source of oxidative stress resulting in eNOS uncoupling, thus providing a mechanism of eNOS uncoupling and endothelial dysfunction in hypercholesterolemia-induced ED.
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