Abstract
ObjectiveTo understand the molecular pathways underlying the cardiac preconditioning effect of short-term caloric restriction (CR).BackgroundLifelong CR has been suggested to reduce the incidence of cardiovascular disease through a variety of mechanisms. However, prolonged adherence to a CR life-style is difficult. Here we reveal the pathways that are modulated by short-term CR, which are associated with protection of the mouse heart from ischemia.MethodsMale 10-12 wk old C57bl/6 mice were randomly assigned to an ad libitum (AL) diet with free access to regular chow, or CR, receiving 30% less food for 7 days (d), prior to myocardial infarction (MI) via permanent coronary ligation. At d8, the left ventricles (LV) of AL and CR mice were collected for Western blot, mRNA and microRNA (miR) analyses to identify cardioprotective gene expression signatures. In separate groups, infarct size, cardiac hemodynamics and protein abundance of caspase 3 was measured at d2 post-MI.ResultsThis short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). mRNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM). Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3ß, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1α, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38). CR regimen was also associated with reduced protein abundance of cleaved caspase 3 in the infarcted heart and improved cardiac function.
Highlights
High-calorie diets and diminished physical activity are environmental factors believed to contribute to the global epidemic of obesity, metabolic disorders and associated cardiovascular diseases (CVD) [1]
This short-term model of caloric restriction (CR) was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). mRNA and miR profiles pre-myocardial infarction (MI) (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, PLOS ONE | DOI:10.1371/journal.pone
In the current study we have demonstrated that short-term (7d) CR protects the mouse heart against ischemic injury with reduced infarct size and cleaved caspase-3 induction at 2d postMI, with improved survival and cardiac hemodynamics
Summary
High-calorie diets and diminished physical activity are environmental factors believed to contribute to the global epidemic of obesity, metabolic disorders and associated cardiovascular diseases (CVD) [1]. Among numerous proposed strategies to reduce CVD, dietary interventions associated with weight loss seem promising. In experimental animals, even a small change in diet content has been shown to have a significant beneficial effect on CVD [2,3,4]. An effective and reproducible intervention for protection of the cardiovascular system is caloric restriction (CR). Since 1935, long-term CR has been known to exert an anti-aging effect, extending average and maximum life span and delaying the onset of age-associated pathologies in rat [6]. We reveal the pathways that are modulated by short-term CR, which are associated with protection of the mouse heart from ischemia
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