Alfonso Gómez Del Val, Ana Sánchez, Óscar Freire-Agulleiro, María Pilar Martínez, Mercedes Muñoz, Lucia Olmos, Javier Sáenz Medina, Gabriel Comerma-Steffensen, Ulf Simonsen, Luis Rivera, Miguel López, Cristina Contreras, Dolores Prieto
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引用次数: 0
摘要
目的：勃起功能障碍（ED）被认为是心血管疾病（CVD）的早期表现：勃起功能障碍（ED）被认为是心血管疾病（CVD）的早期表现，内皮功能障碍是连接心血管疾病和血管性 ED 的纽带。线粒体活性氧（mtROS）与代谢紊乱引起的血管并发症有关。本研究旨在评估肥胖对阴茎勃起组织内皮功能、氧化还原代谢和线粒体生物能的影响：用 mitoSOX（O2.-）和 Amplex Red（H2O2）荧光测定法测量 mtROS 水平，并检测线粒体抗氧化剂 mitoTempo 对内皮依赖性松弛的影响。用 Agilent Seahorse XF Pro 分析仪评估了完整微动脉的线粒体呼吸，并通过 Western 印迹分析了线粒体调节因子和内质网（ER）应激标记物的表达：HFD阴茎动脉对乙酰胆碱（ACh）和线粒体KATP通道激活剂BMS191095的内皮依赖性松弛作用降低。在HFD勃起组织中，mtROS水平显著升高，并与内皮NADPH氧化酶4（Nox4）和过氧化物酶体增殖激活受体γ辅助激活剂1-α（PGC-1α）的上调有关。MitoTempo 可抑制对照组和高脂蛋白血症阴茎动脉的内皮松弛。HFD阴茎动脉的生物能谱明显降低。在肥胖大鼠的勃起组织中，ER应激标记物的蛋白表达增强：结论：线粒体功能障碍、生物能受损和线粒体KATP通道介导的松弛功能降低是肥胖症患者勃起组织内皮和血管功能障碍的原因，尽管有一种补偿机制可增强Nox4衍生的内皮血管扩张剂mtROS。旨在稳定线粒体的治疗策略可以恢复氧化还原平衡，改善线粒体的生物能，从而预防氧化应激和血管功能障碍，这些都是与代谢性疾病相关的 ED 的根本原因。
Penile endothelial dysfunction, impaired redox metabolism and blunted mitochondrial bioenergetics in diet-induced obesity: compensatory role of H2O2.
Objective: Erectile dysfunction (ED) is considered an early manifestation of cardiovascular disease (CVD), endothelial dysfunction being the link between CVD and vasculogenic ED. Mitochondrial reactive oxygen species (mtROS) have been involved in the vascular complications of metabolic disorders. The aim of this study was to assess the impact of obesity on endothelial function, redox metabolism and mitochondrial bioenergetics of penile erectile tissue.
Methods: Wistar rats were fed a high-fat diet (HFD) or standard diet (STD), and penile vascular function was assessed in microvascular myographs. mtROS levels were measured by mitoSOX (O2.-) and Amplex Red (H2O2) fluorimetry, and the effect of the mitochondrial antioxidant mitoTempo on endothelium-dependent relaxations was tested. Mitochondrial respiration of intact microarteries was assessed with an Agilent Seahorse XF Pro analyzer, and the expression of mitochondria regulators and endoplasmic reticulum (ER) stress markers was analyzed by Western blot.
Results: Endothelium-dependent relaxations to acetylcholine (ACh) and to the mitoKATP channel activator BMS191095 were reduced in penile arteries from HFD. mtROS levels were significantly increased and associated with upregulation of the endothelial NADPH oxidase 4 (Nox4) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in HFD erectile tissue. MitoTempo inhibited endothelial relaxations in control and HFD penile arteries. The bioenergetic profile was significantly reduced in HFD penile arteries. Protein expression of ER stress markers was enhanced in erectile tissue of obese rats.
Conclusions: Mitochondrial dysfunction with impaired bioenergetics and reduced mitoKATP channel-mediated relaxation underlie endothelial and vascular dysfunction of erectile tissue in obesity, despite a compensatory mechanism that enhances Nox4-derived endothelial vasodilator mtROS. Therapeutic strategies aimed to stabilize mitochondria could restore redox balance and improve mitochondrial bioenergetics thus preventing oxidative stress and vascular dysfunction underlying metabolic disease associated ED.
期刊介绍：
Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.
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