Katare Rajesh G, Kakinuma Yoshihiko, Arikawa Mikihiko, Yamasaki Fumiyasu, Sato Takayuki
Department of Cardiovascular Control, Kochi Medical School, Nankoku, Kochi, Japan.
J Mol Cell Cardiol. 2009 Mar;46(3):405-12. doi: 10.1016/j.yjmcc.2008.10.027. Epub 2008 Nov 12.
Chronic heart failure (CHF) is the major cause of death in the developed countries. Calorie restriction is known to improve the recovery in these patients; however, the exact mechanism behind this protective effect is unknown. Here we demonstrate the activation of cell survival PI3kinase/Akt and VEGF pathway as the mechanism behind the protection induced by intermittent fasting in a rat model of established chronic myocardial ischemia (MI). Chronic MI was induced in rats by occlusion of the left coronary artery. Two weeks later, the rats were randomly assigned to a normal feeding group (MI-NF) and an alternate-day feeding group (MI-IF). After 6 weeks of observation, we evaluated the effect of intermittent fasting on cellular and ventricular remodeling and long-term survival after CHF. Compared with the normally fed group, intermittent fasting markedly improved the survival of rats with CHF (88.5% versus 23% survival, P<0.05). The heart weight body weight ratio was significantly less in the MI-IF group compared to the MI-NF group (3.4+/-0.17 versus 3.9+/-0.18, P<0.05). Isolated heart perfusion studies exhibited well preserved cardiac functions in the MI-IF group compared to the MI-NF group (P<0.05). Molecular studies revealed the upregulation of angiogenic factors such asHIF-1-alpha (3010+/-350% versus 650+/-151%), BDNF (523+/-32% versus 110+/-12%), and VEGF (450+/-21% versus 170+/-30%) in the fasted hearts. Immunohistochemical studies confirmed increased capillary density (P<0.001) in the border area of the ischemic myocardium and synthesis VEGF by cardiomyocytes. Moreover fasting also upregulated the expression of other anti-apoptotic factors such as Akt and Bcl-2 and reduced the TUNEL positive apoptotic nuclei in the border zone. Chronic intermittent fasting markedly improves the long-term survival after CHF by activation through its pro-angiogenic, anti-apoptotic and anti-remodeling effects.
慢性心力衰竭（CHF）是发达国家主要的死亡原因。已知热量限制可改善这些患者的恢复情况；然而，这种保护作用背后的确切机制尚不清楚。在此，我们证明细胞存活PI3激酶/蛋白激酶B（Akt）和血管内皮生长因子（VEGF）通路的激活是间歇性禁食对已建立的慢性心肌缺血（MI）大鼠模型产生保护作用的机制。通过结扎左冠状动脉在大鼠中诱导慢性MI。两周后，将大鼠随机分为正常喂养组（MI-NF）和隔日喂养组（MI-IF）。观察6周后，我们评估了间歇性禁食对CHF后细胞和心室重塑以及长期存活的影响。与正常喂养组相比，间歇性禁食显著提高了CHF大鼠的存活率（存活率分别为88.5%和23%，P<0.05）。与MI-NF组相比，MI-IF组的心脏重量与体重比显著降低（3.4±0.17对3.9±0.18，P<0.05）。与MI-NF组相比，离体心脏灌注研究显示MI-IF组的心脏功能得到良好保留（P<0.05）。分子研究表明，禁食心脏中血管生成因子如缺氧诱导因子-1α（HIF-1α）（3010±350%对650±151%）、脑源性神经营养因子（BDNF）（523±32%对110±12%）和VEGF（450±21%对170±30%）上调。免疫组织化学研究证实缺血心肌边缘区的毛细血管密度增加（P<0.001）以及心肌细胞合成VEGF。此外，禁食还上调了其他抗凋亡因子如Akt和Bcl-2的表达，并减少了边缘区TUNEL阳性凋亡细胞核。慢性间歇性禁食通过其促血管生成、抗凋亡和抗重塑作用显著提高CHF后的长期存活率。
