Thomas Manesh, Vidal Alex, Bhattacharya Syamal K, Ahokas Robert A, Sun Yao, Gerling Ivan C, Weber Karl T
Division of Cardiovascular Diseases, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2361-6. doi: 10.1152/ajpheart.00200.2007. Epub 2007 Jul 6.
Zinc is a structural constituent of many proteins, including Cu/Zn superoxide dismutase (SOD), an endogenous antioxidant enzyme. Hypozincemia has been found in patients hospitalized with congestive heart failure, where neurohormonal activation, including the renin-angiotensin-aldosterone system (RAAS), is expected and oxidative stress is present. This study was undertaken to elucidate potential pathophysiological mechanisms involved in Zn dyshomeostasis in aldosteronism. In rats receiving aldosterone/salt treatment (ALDOST) alone for 1 and 4 wk or in combination with spironolactone (Spiro), an ALDO receptor antagonist, we monitored 24-h urinary and fecal Zn excretion and tissue Zn levels in heart, liver, and skeletal muscle, together with tissue metallothionein (MT)-I, a Zn(2+)-binding protein, and Cu/Zn-SOD activities in plasma and tissues. When compared with unoperated, untreated, age-/sex-matched controls, urinary and, in particular, fecal Zn losses were markedly increased (P < 0.05) at days 7 and 28 of ALDOST, leading to hypozincemia and a fall (P < 0.05) in plasma Cu/Zn-SOD activity. Microscopic scars and perivascular fibrosis of intramural coronary arteries first appeared in the right and left ventricles at week 4 of ALDOST and were accompanied by increased (P < 0.05) tissue Zn, MT-I, and Cu/Zn-SOD activity, which were not found in uninjured liver or skeletal muscle. Spiro cotreatment prevented cardiac injury and Zn redistribution to the heart. Thus increased urinary and fecal Zn losses, together with their preferential translocation to sites of cardiac injury, where MT-I overexpression and increased Cu/Zn-SOD activity appeared, contribute to Zn dyshomeostasis in rats with aldosteronism, which were each prevented by Spiro. These findings may shed light on Zn dyshomeostasis found in patients with decompensated heart failure.
锌是许多蛋白质的结构成分，包括铜/锌超氧化物歧化酶（SOD），一种内源性抗氧化酶。在因充血性心力衰竭住院的患者中发现了低锌血症，这些患者存在神经激素激活，包括肾素-血管紧张素-醛固酮系统（RAAS），并且存在氧化应激。本研究旨在阐明醛固酮增多症中锌稳态失调所涉及的潜在病理生理机制。在单独接受醛固酮/盐处理（ALDOST）1周和4周或与醛固酮受体拮抗剂螺内酯（Spiro）联合处理的大鼠中，我们监测了24小时尿锌和粪锌排泄以及心脏、肝脏和骨骼肌中的组织锌水平，以及血浆和组织中锌（2 +）结合蛋白金属硫蛋白（MT）-I和铜/锌-SOD活性。与未手术、未治疗、年龄/性别匹配的对照组相比，在ALDOST第7天和28天，尿锌，尤其是粪锌流失显著增加（P < 0.05），导致低锌血症和血浆铜/锌-SOD活性下降（P < 0.05）。ALDOST第4周时，壁内冠状动脉的微观瘢痕和血管周围纤维化首先出现在右心室和左心室，并伴有组织锌、MT-I和铜/锌-SOD活性增加（P < 0.05），而在未受损的肝脏或骨骼肌中未发现这种情况。联合使用螺内酯可预防心脏损伤和锌重新分布到心脏。因此，尿锌和粪锌流失增加，以及它们优先转运到出现MT-I过表达和铜/锌-SOD活性增加的心脏损伤部位，导致醛固酮增多症大鼠出现锌稳态失调，而螺内酯可预防这些情况。这些发现可能有助于解释失代偿性心力衰竭患者中发现的锌稳态失调。
