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INCRETIN AMELIORATES DIABETIC MICROANGIOPATHY IN HEART BY ACTIVATION OF AUTOPHAGY VIA PKA/AMPK AXIS.
Author(s) -
Bando Yasuko,
Monji Akio
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1040.3
Subject(s) - ampk , autophagy , angiogenesis , medicine , endocrinology , chemistry , protein kinase b , enos , protein kinase a , phosphorylation , nitric oxide , nitric oxide synthase , apoptosis , biochemistry
The incretin hormone glucagon‐like peptide‐1 (GLP‐1) restores diabetic myocardial remodeling observed in type 2 diabetic mice (T2DM); however, it remains unclear whether GLP‐1 may modulates angiogenic activity in diabetic heart. Hypothesis We evaluated the impact of GLP‐1 receptor activation on angiogenesis and its link to endothelial autophagy under diabetic condition. Methods T2DM mice were treated with Ex4 (24 nmole/kg/day for 4 weeks). Cardiac capiary density was measured by CD31 immunohistological staining. Cultured ECs were used for in vitro experiments. Analyses for the changes in autophagy (LC3‐turnover assay and protein levels of p62 and Beclin1), and angiogenesis (tube formation assay and Akt/AMPK/eNOS activity), were evaluated with or without molecular‐targetted knockdown by RNA interference (siRNA). Results T2DM exhibited reduced cardiac capillary density in diabetic heart, which was restored by Ex‐4 with increase in myocardial cyclic AMP concentration. GLP‐1 receptor expression in ECs was confirmed by immunoblot and QPCR. Ex‐4 and PKA enhancers (10 μM forskolin and 1 mM 8‐bromo‐cyclic AMP) facilitated angiogenesis and autophagy in ECs. PKA/AMPK/eNOS phosphorylation levels in ECs were enhanced by Ex4, but each Akt activity remains unchanged. PKA inhibitors (H89, RP‐cAMP, and siRNA for PKA) abrogated the increase in AMPK/eNOS phosphorylation induced by Ex‐4. Tube formation assay revealed that Ex4 enhanced in vitro angiogenesis which were abrogated by inhibition of autophagy and AMPK activity. Conclusions GLP‐1 receptor activation by Ex‐4 restores impaired angioogenic activity in diabetic heart via the PKA/AMPK‐dependent endothelial autophagic activation.