Lakhani Hari Vishal, Zehra Mishghan, Pillai Sneha, Shapiro Joseph I, Sodhi Komal
Department of Surgery, Internal Medicine, and Biomedical Sciences, Joan C Edwards School of Medicine, Marshall University, Huntington, United States of America.
J Clin Med Sci. 2024;8(2). Epub 2024 May 20.
Angiotensin II (AngII), a component of the Renin-Angiotensin-Aldosterone System (RAAS), has been implicated in the dysregulation of adipose tissue function. Inhibition of AngII has been shown to improve adipose tissue function in mice with metabolic syndrome. It is well established that the Heme Oxygenase-1 (HO-1), an antioxidant improves oxidative stress and phenotypic change in adipocytes. Molecular effects of high oxidative stress include suppression of Sirtuin-1 (SIRT1), which is amenable to redox manipulations. However, the underlying mechanisms by which the Renin-Angiotensin-Aldosterone System (RAAS) exerts its metabolic effects are not fully understood. In this study, we propose that AngII-induced oxidative stress may suppress adipocyte SIRT1 through down-regulation of HO-1. Consequently, this suppression of SIRT1 may result in the up-regulation of the Mineralocorticoid Receptor (MR). We further hypothesize that the induction of HO-1 would rescue SIRT1, thereby improving oxidative stress and adipocyte phenotype. To establish this hypothesis, we conducted experiments using mouse preadipocytes treated with AngII, in the presence or absence of Cobalt Protoporphyrin (CoPP), an inducer of HO-1, and Tin Mesoporphyrin (SnMP), an inhibitor of HO-1. Our data demonstrate that treatment of mouse preadipocytes with AngII leads to increased lipid accumulation, elevated levels of superoxide and inflammatory cytokines (Interleukin-6 and Tumor necrosis factor alpha), and reduced levels of adiponectin. However, these effects were attenuated by the induction of HO-1, and this attenuation was reversed by SnMP, indicating that the beneficial effects on adipocyte phenotype are modulated by HO-1. Furthermore, our findings reveal that AngII-treated preadipocytes exhibit upregulated MR levels and suppressed expression, which are rescued by HO-1 induction. Following treatment with CoPP and siRNA in mouse preadipocytes resulted in increased lipid accumulation and elevated levels of fatty acid synthase, indicating that the beneficial effects of HO-1 are modulated through SIRT1. Our study provides evidence that HO-1 restores cellular redox balance, rescues SIRT1, and attenuates the detrimental effects of AngII on adipocytes and systemic metabolic profile.
血管紧张素II（AngII）是肾素-血管紧张素-醛固酮系统（RAAS）的一个组成部分，与脂肪组织功能失调有关。已表明抑制AngII可改善患有代谢综合征小鼠的脂肪组织功能。血红素加氧酶-1（HO-1）作为一种抗氧化剂，可改善氧化应激和脂肪细胞的表型变化，这一点已得到充分证实。高氧化应激的分子效应包括抑制沉默调节蛋白1（SIRT1），而SIRT1可通过氧化还原操作进行调节。然而，肾素-血管紧张素-醛固酮系统（RAAS）发挥其代谢作用的潜在机制尚未完全了解。在本研究中，我们提出AngII诱导的氧化应激可能通过下调HO-1来抑制脂肪细胞中的SIRT1。因此，SIRT1的这种抑制可能导致盐皮质激素受体（MR）上调。我们进一步假设，HO-1的诱导将挽救SIRT1，从而改善氧化应激和脂肪细胞表型。为了验证这一假设，我们使用用AngII处理的小鼠前脂肪细胞进行了实验，同时存在或不存在HO-1诱导剂钴原卟啉（CoPP）和HO-1抑制剂锡原卟啉（SnMP）。我们的数据表明，用AngII处理小鼠前脂肪细胞会导致脂质积累增加、超氧化物和炎性细胞因子（白细胞介素-6和肿瘤坏死因子α）水平升高以及脂联素水平降低。然而，HO-1的诱导减弱了这些效应，而SnMP可逆转这种减弱，这表明HO-1对脂肪细胞表型的有益作用受到调节。此外，我们的研究结果表明，用AngII处理的前脂肪细胞表现出MR水平上调和表达受抑制，而HO-1诱导可挽救这种情况。在用CoPP和siRNA处理小鼠前脂肪细胞后，导致脂质积累增加和脂肪酸合酶水平升高，这表明HO-1的有益作用是通过SIRT1调节的。我们的研究提供了证据，表明HO-1可恢复细胞氧化还原平衡，挽救SIRT1，并减轻AngII对脂肪细胞和全身代谢谱的有害影响。
