Introduction:
Ample evidence demonstrates cardiovascular protection by incretin hormone glucagon-like peptide-1 (GLP-1) through the cyclic AMP axis. GLP-1 is known for its inotropic effect on heart, however, the role of GLP-1 in heart failure remains uncertain.
Hypothesis:
To explore the pathophysiological role of GLP-1 in heart failure
Methods:
Pressure overload-induced heart failure model was generated by transverse aortic constriction in mice (TAC).
Results:
At 4 week after the operation, TAC exhibited systolic left-ventricular dysfunction, myocardial hypertrophy and augmented apoptosis. Unexpectedly, circulating GLP-1 concentration was markedly decreased in TAC (in pM; 0.86±0.10 for TAC versus 2.13±0.54 for sham) with concomitant reduction of myocardial cyclic AMP concentration (in pmole/mg protein; 33.0±1.4 for TAC versus 42.2±1.5). TAC exhibited pathological changes in signaling molecules of myocardial contractility [SERCA, phospho-phospholamban(Serine16; pPL), β-myosin heavy chain (MYH7)], remodeling (Akt/mTOR/S6K), and cell death markers (procaspase-3/Bcl2 for apoptosis and PINK/PARKIN complex for mitophagy detecting damaged mitochondria). All of these changes observed in TAC heart were reversed selectively by treatment with GLP-1 analog exendin-4 (Ex4; 24nmole/kg/day for 4 weeks) and indirect supplement of GLP-1 by a DPP4 inhibitor alogliptin (ALO; 10mg/kg/day for 4 weeks). In vitro TUNEL assay using cultured cardiomyocytes revealed that Ex-4 reduced myocardial apoptosis in a cAMP/EPAC1-dependent but PKA-independent manner (Figure).
Conclusions:
Pressure-overloaded heart failure exhibits decline in GLP-1, leading to cAMP/EPAC1-dependent impairment in myocardial apoptosis, and cAMP/PKA/pPL/SERCA-dependent myocardial contractile dysfunction. Our data suggest the distinct role of PKA and EPAC in pathophysiology underlying heart failure.
Ileal short-chain fatty acids inhibit gastric motility by a humoral pathway
