Abstract 13657: GLP-1[28-36] Exerts Direct Cardioprotective Effects, Activating Pro-Survival Kinases and Soluble Adenylyl Cyclase
Background: GLP-1[7-36] (GLP-1), an incretin hormone that regulates glucose homeostasis, is rapidly degraded to GLP-1[9-36]. Both GLP-1 and [9-36] are cardioprotective against ischemia-reperfusion (I/R) injury in wild-type and GLP-1 receptor knockout mice. GLP-1 and [9-36] are believed to be cleaved by neutral endopeptidase 24.11 to release the nanopeptide GLP-1[28-36]. While shown to have glucoregulatory effects, the cardiovascular effects of [28-36] were not known.
Methods: Isolated hearts (male C57BL6/J mice, 10-12 wk old) underwent 30 min of global ischemia and 40 min of reperfusion. Vehicle, [28-36], and parent peptides, GLP-1 and [9-36], were administered for 20 min pre-ischemia. Recovery of cardiac performance was assessed as % LV developed pressure (LVDP) post-reperfusion. Hearts lysates were processed for Western blot. Separate groups were infused with the same treatments for 14 d by osmotic minipumps, followed by LAD ligation-induced MI. At 4 d post-MI, infarct size was evaluated with 2,3,5-tetrazolium chloride staining. Cellular actions of [28-36] were also examined in primary human coronary smooth muscle cells (hCSMCs).
Results: Recovery of LVDP was significantly greater in [28-36]- vs. vehicle-treated hearts (57.6±6.6%, n=12 vs. 22.7±3.6%, n=13; P<0.05), and comparable to GLP-1 and [9-36] (67.3±8.6%, n=13 and 64.3±9.6%, n=8 respectively). Western blots showed that [28-36] enhanced activation of Akt, Erk1/2, CREB and eNOS. In the MI model, treatment with [28-36] significantly reduced infarct size vs. vehicle controls (24.9±2.4% n=7 vs. 34.4±2.8% n=7, P<0.05). In hCSMCs, [28-36] caused dose-dependent increases in intracellular cAMP, an effect blocked by soluble adenylyl cyclase (AC) inhibitor KH7, but not transmembrane AC inhibitor 2’,5’-dideoxyadenosine.
Conclusion: GLP-1[28-36] exerts a myocardial pre-conditioning effect in both an I/R injury model ex vivo, and a chronic ischemia model in vivo. This small peptide activated pro-survival kinases in the mouse heart and stimulated soluble AC-dependent cAMP production in hCSMCs. These data suggest that even short metabolites of GLP-1 have important biological effects on the cardiovascular system, and may explain its GLP-1 receptor-independent effects.
- © 2012 by American Heart Association, Inc.