Abstract
Background: Caloric restriction (CR) promotes beneficial cardiovascular effects; however, its effects on cardiac angiogenesis remain unclear. We thus examined whether CR may modulate cardiac angiogenesis via activation of autophagy and seeked for the essential nutrient factor(s) that may be responsible for the CR-mediated angiogenesis. Methods: To confirm whether CR-induced angiogenic effects may be universally observed, we allocated 2 distinct heart failure models; #1 pressure overload (4 weeks) generated by transaortic constriction (TAC) and #2 diet-induced obesity (DIO) mice, as a model of diabetic cardiomyopathy. Male mice (14 w/o) were randomly allocated to a 4-week CR (TAC-CR and DIO-CR) and ad libitum (TAC-AL and DIO-AL). Cultured endothelial cells (ECs) were exposed to culture media of 1) ordinary composition, 2) glucose-depleted, 3) amino acid-depleted, and 4) serum-depleted condition. To visualize cardiac autophagic changes, GFP-LC3 mice were allocated to DIO and TAC treatment. Analyses for the changes in activities of autophagy (LC3-turnover assay and p62 level) and angiogenesis (tube formation and Akt/AMPK/eNOS activity) were evaluated. Results: Immunohistochemical analyses revealed that CR enhanced cardiac angiogenesis both in TAC and DIO mice. CR promoted increased in myocardial cyclic AMP concentration with concomitant PKA/AMPK/eNOS activation and the simultaneous increase in autophagic activity both in TAC and DIO hearts. Of note, cardiac Akt activity remains unchanged by CR. In vitro analysis revealed that glucose depletion, as well as forskolin (10 μM) and 8-bromo-cyclic AMP (1 mM), activated PKA/AMPK axis thereby facilitated angiogenesis and autophagy in ECs. The enhanced in vitro angiogenesis induced by glucose depletion and PKA enhancers was abrogated by autophagy inhibitor 3-MA treatment. PKA inhibitors (H89 and RP-cAMP) abrogated the increase in AMPK/eNOS phosphorylation levels induced by glucose depletion. Neither amino acid- nor serum-depletion had no effect on angiogenesis and autophagy. Conclusions: Glucose depletion is essential for the CR-mediated activation of cardiac angiogenesis and autophagy in a cAMP/PKA/AMPK-dependent fashion.
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