Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes

Abstract

Glucagon-like peptide (GLP)-1 receptor activation increases intracellular cAMP with downstream activation of PKA. Cilostazol (CIL), a phosphodiesterase-3 inhibitor, prevents cAMP degradation. We assessed whether CIL amplifies the exenatide (EX)-induced increase in myocardial cAMP levels and PKA activity and augments the infarct size (IS)-limiting effects of EX in db/db mice. Mice fed a Western diet received oral CIL (10 mg/kg) or vehicle by oral gavage 24 h before surgery. One hour before surgery, mice received EX (1 μg/kg sc) or vehicle. Additional mice received H-89, a PKA inhibitor, alone or with CIL + EX. Mice underwent 30 min of coronary artery occlusion and 24 h of reperfusion. Both EX and CIL increased myocardial cAMP levels and PKA activity. Levels were significantly higher in the EX + CIL group. Both EX and CIL reduced IS. IS was the smallest in the CIL + EX group. H-89 completely blocked the IS-limiting effects of EX + CIL. EX + CIL decreased phosphatase and tensin homolog on chromosome 10 upregulation and increased Akt and ERK1/2 phosphorylation after ischemia-reperfusion. These effects were blocked by H-89. In conclusion, EX and CIL have additive effects on IS limitation in diabetic mice. The additive effects are related to cAMP-induced PKA activation, as H-89 blocked the protective effect of CIL + EX.

Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

“…Currently available PDE3 inhibitors have little or no selectivity for PDE3A versus PDE3B, because the catalytic domains of PDE3A and PDE3B are very similar. In mice with type 2 diabetes, cilostazol enhanced the ability of exenatide and a dipeptidyl-peptidase-4 inhibitor to limit the extent of IR injury (70,71). Given these reports and our findings of cardioprotection in PDE3B −/− mice, PDE3B-selective inhibitors might provide benefit in heart transplant patients and heart failure patients, and perhaps in type 2 diabetics, by limiting I/R damage.…”

Dipeptidyl peptidase-4 inhibition by Saxagliptin prevents inflammation and renal injury by targeting the Nlrp3/ASC inflammasome

“…14 15 Our group has previously shown that GLP-1 receptor agonists and DPP4Is increased the production of 15-epi-lipoxin A 4 , an arachidonic acid mediator with potent anti-inflammatory and inflammation resolution properties via activation of protein kinase A and 5-lipoxygenase. 41 42 15-Epi-lipoxin A 4 suppressed activation of the inflammasome. 43 44 Thus, inhibition of the inflammasome in our models might be explained by 15-epi-lipoxin A 4 .…”

Cyclic AMP-mediated pleiotropic effects of glucagon-like peptide-1 receptor activation. Focus on “Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a”

“…The protective effect was completely blocked by PKA inhibitors, suggesting that PKA mediates the protective effect of GLP1 receptor activation (1,13).…”

“…The precise signaling pathway for the alteration in SERCA2a expression has not yet been clarified. We have recently shown that PKA controls phosphatase and tensin homolog on chromosome 10 (PTEN) levels (1,13). PTEN degrades phosphatidylinositol 3-phosphate (PI3P) that is produced by phosphoinositide 3-kinase (PI3K).…”