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Mitochondrial DNA integrity and function are critical for endothelium-dependent vasodilation in rats with metabolic syndrome
Basic Research in Cardiology ( IF 9.5 ) Pub Date : 2022-01-17 , DOI: 10.1007/s00395-021-00908-1
Takahiko Kiyooka 1 , Vahagn Ohanyan 2 , Liya Yin 2 , Yuh Fen Pung 3 , Yeong-Renn Chen 2 , Chwen-Lih Chen 2 , Patrick T Kang 2 , James P Hardwick 2 , June Yun 2 , Danielle Janota 2 , Joanna Peng 2 , Christopher Kolz 2 , Giacinta Guarini 4 , Glenn Wilson 5 , Inna Shokolenko 5 , Donte A Stevens 6 , William M Chilian 2
Affiliation  

Endothelial dysfunction in diabetes is generally attributed to oxidative stress, but this view is challenged by observations showing antioxidants do not eliminate diabetic vasculopathy. As an alternative to oxidative stress-induced dysfunction, we interrogated if impaired mitochondrial function in endothelial cells is central to endothelial dysfunction in the metabolic syndrome. We observed reduced coronary arteriolar vasodilation to the endothelium-dependent dilator, acetylcholine (Ach), in Zucker Obese Fatty rats (ZOF, 34 ± 15% [mean ± standard deviation] 10–3 M) compared to Zucker Lean rats (ZLN, 98 ± 11%). This reduction in dilation occurred concomitantly with mitochondrial DNA (mtDNA) strand lesions and reduced mitochondrial complex activities in the endothelium of ZOF versus ZLN. To demonstrate endothelial dysfunction is linked to impaired mitochondrial function, administration of a cell-permeable, mitochondria-directed endonuclease (mt-tat-EndoIII), to repair oxidatively modified DNA in ZOF, restored mitochondrial function and vasodilation to Ach (94 ± 13%). Conversely, administration of a cell-permeable, mitochondria-directed exonuclease (mt-tat-ExoIII) produced mtDNA strand breaks in ZLN, reduced mitochondrial complex activities and vasodilation to Ach in ZLN (42 ± 16%). To demonstrate that mitochondrial function is central to endothelium-dependent vasodilation, we introduced (via electroporation) liver mitochondria (from ZLN) into the endothelium of a mesenteric vessel from ZOF and restored endothelium-dependent dilation to vasoactive intestinal peptide (VIP at 10–5 M, 4 ± 3% vasodilation before mitochondrial transfer and 48 ± 36% after transfer). Finally, to demonstrate mitochondrial function is key to endothelium-dependent dilation, we administered oligomycin (mitochondrial ATP synthase inhibitor) and observed a reduction in endothelium-dependent dilation. We conclude that mitochondrial function is critical for endothelium-dependent vasodilation.



中文翻译:

线粒体 DNA 的完整性和功能对于代谢综合征大鼠的内皮依赖性血管舒张至关重要

糖尿病中的内皮功能障碍通常归因于氧化应激,但这一观点受到表明抗氧化剂不能消除糖尿病血管病变的观察结果的挑战。作为氧化应激引起的功能障碍的替代方案,我们询问内皮细胞中受损的线粒体功能是否是代谢综合征中内皮功能障碍的核心。我们观察到 Zucker 肥胖肥胖大鼠(ZOF,34 ± 15% [平均值 ± 标准偏差] 10 –3 M) 与 Zucker Lean 大鼠 (ZLN, 98 ± 11%) 相比。ZOF 与 ZLN 相比,这种扩张减少伴随着线粒体 DNA (mtDNA) 链损伤和线粒体复合物活性降低。为了证明内皮功能障碍与线粒体功能受损有关,使用细胞可渗透的线粒体定向核酸内切酶 (mt-tat-EndoIII) 修复 ZOF 中氧化修饰的 DNA,恢复线粒体功能并舒张 Ach (94 ± 13%) ). 相反,施用细胞可渗透的、线粒体定向的核酸外切酶 (mt-tat-ExoIII) 在 ZLN 中产生 mtDNA 链断裂,减少线粒体复合物活性和 ZLN 中 Ach 的血管舒张 (42 ± 16%)。为了证明线粒体功能是内皮依赖性血管舒张的核心,–5  M,线粒体转移前血管舒张 4 ± 3%,转移后血管舒张 48 ± 36%)。最后,为了证明线粒体功能是内皮依赖性扩张的关键,我们给予寡霉素(线粒体 ATP 合酶抑制剂)并观察到内皮依赖性扩张的减少。我们得出结论,线粒体功能对内皮依赖性血管舒张至关重要。

更新日期:2022-01-18
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