Antiarrhythmic Effects of Melatonin and Omega-3 Are Linked with Protection of Myocardial Cx43 Topology and Suppression of Fibrosis in Catecholamine Stressed Normotensive and Hypertensive Rats
Antiarrhythmic Effects of Melatonin and Omega-3 Are Linked with Protection of Myocardial Cx43 Topology and Suppression of Fibrosis in Catecholamine Stressed Normotensive and Hypertensive Rats
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DOI：
10.3390/antiox9060546
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发表时间：
2020-06-01
期刊：
影响因子：
7
通讯作者：
Tribulova, Narcisa
中科院分区：
文献类型：
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作者：
Bacova, Barbara Szeiffova;Viczenczova, Csilla;Tribulova, Narcisa
心脏β-肾上腺素能过度刺激导致氧化应激、肥大、缺血、病变和纤维化，使心脏易受恶性心律失常的影响。我们的目的是探讨抗氧化和抗炎化合物，褪黑激素，和ω-3，在正常血压和高血压大鼠暴露于异丙肾上腺素（ISO）诱导的β-肾上腺素能受体激动剂的抗炎疗效，及其作用机制。8个月大的雄性SHR和Wistar大鼠在7天内注射ISO（累积剂量，118 mg/kg）。ISO大鼠未经处理或伴随用褪黑激素（10 mg/kg/天）或ω-3（Omacor，1.68 g/kg/天）处理，直至ISO戒断60天，并与非ISO对照组进行比较。研究结果表明，褪黑激素和欧米茄-3增加阈值电流，诱导心室颤动（VF）在ISO大鼠，无论应变。这些化合物的长期治疗导致ISO诱导的细胞外基质改变的显著抑制，如弥漫性纤维化面积减少和羟脯氨酸、胶原蛋白-1、SMAD 2/3和TGF-β 1蛋白水平下降所示。重要的是，在Wistar和SHR心脏中，褪黑激素和omega-3显著减弱了高促肾上腺皮质激素ISO诱导的电偶联蛋白连接蛋白43（Cx43）分布紊乱及其重塑（偏侧化）。平行地，两种化合物阻止了在丝氨酸368处磷酸化的Cx43变体与PKC β一起沿着的ISO后相关增加，这已知调节Cx43重塑。褪黑激素和欧米茄-3增加SOD 1或SOD 2蛋白水平在ISO暴露大鼠的两个菌株。总之，这些结果表明，褪黑素和ω-3的抗心肌炎作用可能归因于在正常血压和高血压大鼠中由儿茶酚胺β诱导的氧化应激的设置中保护心肌Cx43拓扑结构和抑制纤维化。
Cardiac beta-adrenergic overstimulation results in oxidative stress, hypertrophy, ischemia, lesion, and fibrosis rendering the heart vulnerable to malignant arrhythmias. We aimed to explore the anti-arrhythmic efficacy of the anti-oxidative and anti-inflammatory compounds, melatonin, and omega-3, and their mechanisms of actions in normotensive and hypertensive rats exposed to isoproterenol (ISO) induced beta-adrenergic overdrive. Eight-month-old, male SHR, and Wistar rats were injected during 7 days with ISO (cumulative dose, 118 mg/kg). ISO rats were either untreated or concomitantly treated with melatonin (10 mg/kg/day) or omega-3 (Omacor, 1.68 g/kg/day) until 60 days of ISO withdrawal and compared to non-ISO controls. Findings showed that both melatonin and omega-3 increased threshold current to induce ventricular fibrillation (VF) in ISO rats regardless of the strain. Prolonged treatment with these compounds resulted in significant suppression of ISO-induced extracellular matrix alterations, as indicated by reduced areas of diffuse fibrosis and decline of hydroxyproline, collagen-1, SMAD2/3, and TGF-beta 1 protein levels. Importantly, the highly pro-arrhythmic ISO-induced disordered cardiomyocyte distribution of electrical coupling protein, connexin-43 (Cx43), and its remodeling (lateralization) were significantly attenuated by melatonin and omega-3 in Wistar as well as SHR hearts. In parallel, both compounds prevented the post-ISO-related increase in Cx43 variant phosphorylated at serine 368 along with PKC epsilon, which are known to modulate Cx43 remodeling. Melatonin and omega-3 increased SOD1 or SOD2 protein levels in ISO-exposed rats of both strains. Altogether, the results indicate that anti-arrhythmic effects of melatonin and omega-3 might be attributed to the protection of myocardial Cx43 topology and suppression of fibrosis in the setting of oxidative stress induced by catecholamine overdrive in normotensive and hypertensive rats.