Chronic intermittent fasting improves the survival following large myocardial ischemia by activation of BDNF/VEGF/PI3K signaling pathway.
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.
Katare
Rajesh G
RG
Department of Cardiovascular Control, Kochi Medical School, Nankoku, Kochi, Japan. katarerajesh@yahoo.com
Kakinuma
Yoshihiko
Y
Arikawa
Mikihiko
M
Yamasaki
Fumiyasu
F
Sato
Takayuki
T
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D031204:Caloric Restriction; D002908:Chronic Disease; D004789:Enzyme Activation; D005215:Fasting / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism / Q000401:mortality; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D019208:Brain-Derived Neurotrophic Factor; D009124:Muscle Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt