aInstitute for Heart Research, Slovak Academy of Sciences bFaculty of Medicine, Institute of Physiology, Comenius University cInstitute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia dFaculty of Science, Department of Physiology, Charles University eInstitute of Physiology, v.v.i., Academy of Sciences of Czech Republic, Prague, Czech Republic fThe National Cardiovascular Institute, Bratislava, Slovakia *Jana Radosinska and Barbara Bacova contributed equally to the writing of the article.
J Hypertens. 2013 Sep;31(9):1876-85. doi: 10.1097/HJH.0b013e328362215d.
Hypertension-induced myocardial remodeling is known to be associated with increased risk for malignant arrhythmias and alterations in electrical coupling protein, connexin-43 (Cx43), may be involved. We investigated whether omega-3 fatty acids intake affects abnormalities of Cx43 as well as protein kinase C (PKC) signaling and myosin heavy chain (MyHC) profile at the early and late stage of hypertension in the context of the heart's susceptibility to ventricular fibrillation and ability to restore sinus rhythm.
Untreated young and old male spontaneously hypertensive rats (SHRs) and age-matched normotensive rats were compared with animals supplemented by omega-3 (eicosapentaneoic acid + docosahexaneoic acid, 200 mg/kg body weight/day) for 2 months. Left ventricular tissues were taken for examination of subcellular integrity of gap junctions, Cx43 mRNA and protein expression, PKCε and PKCδ as well as MyHC determination. Electrically inducible ventricular fibrillation and sinus rhythm restoration (SRR) were examined on Langedorff-perfused heart preparation.
Omega-3 intake significantly reduced cardiovascular risk factors, suppressed inducible ventricular fibrillation, and facilitated SRR in hypertensive rats. Supplementation attenuated lateralization and internalization of Cx43, suppressed elevated Cx43 mRNA, enhanced total Cx43 protein expression and/or expression of its functional phosphorylated forms as well as the expression of cardioprotective PKC-ε and suppressed pro-apoptotic PKC-δ isoform. Moreover, the omega-3 diet normalized MyHC profiles in SHR at early stage of disease and old nonhypertensive rats, but failed to do so in old SHR at late stage of disease.
Findings suggest that amelioration of myocardial Cx43-related abnormalities, positive modulation of PKC pathways, and normalization of MyHC can significantly contribute to the antiarrhythmic effects of omega-3 in rat model mimicking human essential hypertension. Our results support the prophylactic use of omega-3 to minimize cardiovascular risk and sudden arrhythmic death.
高血压引起的心肌重构与恶性心律失常风险增加有关，连接蛋白 43（Cx43）的电偶联蛋白改变可能与之相关。我们研究了ω-3 脂肪酸摄入是否会影响高血压早期和晚期 Cx43 以及蛋白激酶 C（PKC）信号和肌球蛋白重链（MyHC）谱的异常，同时研究了心脏易发生室颤和恢复窦性节律的能力。
比较了未经治疗的年轻和年老雄性自发性高血压大鼠（SHR）和年龄匹配的正常血压大鼠，以及补充ω-3（二十碳五烯酸+二十二碳六烯酸，200mg/kg 体重/天）2 个月的动物。取左心室组织检查缝隙连接亚细胞完整性、Cx43 mRNA 和蛋白表达、PKCε和 PKCδ以及 MyHC 测定。用电刺激 Langendorff 灌流心脏制备检查可诱导性室颤和窦性节律恢复（SRR）。
ω-3 摄入显著降低了高血压大鼠的心血管危险因素，抑制了可诱导性室颤，并促进了 SRR。补充剂减弱了 Cx43 的侧向化和内化，抑制了 Cx43 mRNA 的升高，增强了总 Cx43 蛋白表达和/或其功能磷酸化形式的表达以及保护性 PKC-ε的表达，并抑制了促凋亡 PKC-δ同工型。此外，ω-3 饮食在疾病早期正常化了 SHR 的 MyHC 谱，也正常化了非高血压老年大鼠的 MyHC 谱，但在疾病晚期未能正常化 SHR 的 MyHC 谱。
研究结果表明，改善心肌 Cx43 相关异常、正性调节 PKC 通路以及正常化 MyHC 可显著有助于ω-3 在模拟人类原发性高血压的大鼠模型中的抗心律失常作用。我们的结果支持预防性使用ω-3 以最大限度地降低心血管风险和猝死的风险。
