Reduced nNOS activity is responsible for impaired fatty acid-dependent mitochondrial oxygen consumption in atrial myocardium from hypertensive rat.
Reduced nNOS activity is responsible for impaired fatty acid-dependent mitochondrial oxygen consumption in atrial myocardium from hypertensive rat.
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nNOS 活性降低导致高血压大鼠心房肌中脂肪酸依赖性线粒体耗氧量受损。
DOI：
10.1007/s00424-020-02435-9
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Yin Hua Zhang
中科院分区：
文献类型：
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作者：
Yu Na Wu;Chun Li Jin;Ji Hyun Jang;Zai Hao Zhao;Sung Joon Kim;Yin Hua Zhang
高血压（HTN）心房肌脂肪酸（FA）依赖的线粒体活性及其受一氧化氮（NO）的调节尚不清楚。在这里，我们研究了棕榈酸（PA）的调节心脏线粒体耗氧率（OCR）在假手术和血管紧张素II诱导HTN大鼠左心房（LA）心肌和他们的监管内皮型一氧化氮合酶（eNOS）和神经型一氧化氮合酶（nNOS）。与左心室（LV）心肌细胞的效果进行了比较。我们的研究结果表明，OCR是更大的HTN-LA与假LA相比。PA增加假LA、假LV和HTN-LV的OCR，但降低HTN-LA的OCR。抑制nNOS（S-甲基-L-硫代瓜氨酸，SMTC）或eNOS/nNOS（Nω-硝基-L-精氨酸甲酯盐酸盐，L-NAME）均能降低假LA OCR的PA增量，但对HTN LA的OCR无影响。SMTC降低HTN-LV的OCR，L-NAME降低假LV的OCR。nNOS是LA和LV NO的主要来源。HTN-LA和HTN-LV中nNOS衍生的NO增加。PA降低HTN-LA的eNOSSer 1177、nNOSSer 1417和NO水平，但对假LA无影响。与此相反，PA增加HTN-LV中的NO和增强nNOSSer 1417，但降低假LV中的NO水平，而不影响eNOSSer 1177、eNOSThr 495或nNOSSer 1417。2-溴棕榈酸酯（2BP），它阻止了目标蛋白的S-棕榈酰化，防止了PA依赖性的减少nNOSSer 1417和OCR在HTN-LA。在HTN-LV中，2BP阻止PA诱导的OCR而不影响nNOSSer 1417。我们的研究结果表明，FA诱导的心房心肌线粒体活性受损HTN介导的nNOS活性和NO的生物利用度降低。代谢紊乱可能是HTN患者心房肌舒张功能障碍的基础。
Fatty acid (FA)-dependent mitochondrial activities of atrial myocardium in hypertension (HTN) and its regulation by nitric oxide (NO) remain unidentified. Here, we have studied palmitic acid (PA) regulation of cardiac mitochondrial oxygen consumption rate (OCR) in left atrial (LA) myocardium of sham and angiotensin II-induced HTN rats and their regulations by endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS). The effects were compared with those of left ventricular (LV) myocytes. Our results showed that OCR was greater in HTN-LA compared with that in sham-LA. PA increased OCR in sham-LA, sham-LV, and HTN-LV but reduced it in HTN-LA. Inhibition of nNOS (S-methyl-L-thiocitrulline, SMTC) or eNOS/nNOS (Nω-nitro-L-arginine methyl ester hydrochloride, L-NAME) reduced PA increment of OCR in sham-LA but exerted no effect on OCR in HTN-LA. SMTC reduced OCR in HTN-LV and L-NAME reduced OCR in sham-LV. nNOS was the predominant source of NO in LA and LV. nNOS-derived NO was increased in HTN-LA and HTN-LV. PA reduced eNOSSer1177, nNOSSer1417, and NO level in HTN-LA but exerted no effect in sham-LA. In contrast, PA increased NO in HTN-LV and enhanced nNOSSer1417 but reduced NO level in sham-LV without affecting eNOSSer1177, eNOSThr495, or nNOSSer1417. 2-Bromopalmitate (2BP), which blocks the S-palmitoylation of target proteins, prevented PA-dependent decrease of nNOSSer1417 and OCR in HTN-LA. In HTN-LV, 2BP prevented PA-induced OCR without affecting nNOSSer1417. Our results reveal that FA-induced mitochondrial activity in atrial myocardium is impaired in HTN which is mediated by reduced nNOS activity and NO bioavailability. Metabolic dysregulation may underlie diastolic dysfunction of atrial myocardium in HTN.