Chronic intermittent fasting improves the survival following large myocardial ischemia by activation of BDNF/VEGF/PI3K signaling pathway

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / biosynthesis*
  • Caloric Restriction
  • Chronic Disease
  • Enzyme Activation
  • Fasting / metabolism*
  • Heart Failure / metabolism
  • Heart Failure / mortality
  • Humans
  • Male
  • Muscle Proteins / metabolism*
  • Myocardial Ischemia / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Rats
  • Rats, Wistar
  • Signal Transduction*
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / biosynthesis*


  • Brain-Derived Neurotrophic Factor
  • Muscle Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt