Prevalent role of Akt and ERK activation in cardioprotective effect of Ca2+ channel- and beta-adrenergic receptor blockers

Abstract

We studied cardioprotective as well as Akt and extracellular signal-activated kinase (ERK) activating effect of a Ca(2+) antagonist and a beta-adrenergic receptor blocker during ischemia-reperfusion, and compared these properties of the substances with that of a poly(ADP-ribose) polymerase (PARP) inhibitor used as a positive control throughout the experiments. Langendorff-perfused isolated rat hearts were subjected to 25 min global ischemia followed by 45 min reperfusion, and recovery of energy metabolism as well as functional cardiac parameters were monitored. Although to varying extents, all substances improved recovery of creatine phosphate, ATP, intracellular pH, and reutilization of inorganic phosphate. These favorable changes were accompanied by improved recovery of heart function parameters and reduced infarct size. In addition and again to varying extents, all studied substances decreased oxidative damage (lipid peroxidation and protein oxidation), and activated Akt, glycogen synthase kinase (GSK)-3beta, and ERK1/2. Correlation between cardioprotective and kinase activating effectivity of the compounds proved to be statistically significant. Physiological significance of these kinase activations was established by demonstrating that inhibition of Akt by LY294002 and ERK1/2 by PD98059 compromised the cardioprotective effect of all the substances studied. In conclusion, we demonstrated for the first time that activation of phosphatidylinositol-3-kinase (PI-3K)-Akt and ERK2 pathways significantly contributed to cardioprotective effects of a Ca(2+) antagonist and a beta-adrenergic receptor blocker. Furthermore, we found a strong correlation between cardioprotective and kinase-activating potencies of the substances studied (Verapamil, Metoprolol and two PARP inhibitors), which indicated the potentiality of these kinases as drug-targets in the therapy of ischemic heart disease.

Salvianolic Acid B Alleviates Heart Failure by Inactivating ERK1/2/GATA4 Signaling Pathway after Pressure Overload in Mice

“…Using Western blot analysis, we found that the ERK1/2 phophsrylations of threonines at 202 th and tyrosine at 204 th sites were enhanced after TAC surgery, compared with control(Fig 4A and 4C, P< 0.001). Moreover, the phosphorylations of threonines at 202th and tyrosine at 204th sites were reduced after metoprolol incubation, consistent with published data [14] . Interestingly, the phosphorylations of ERK1/2 was blocked after SalB stimulation(P<0.001, Fig 4A and 4C).…”

The role of reactive oxygen species in the pathophysiology of cardiovascular diseases and the clinical significance of myocardial redox

“…Various experimental data demonstrated the beneficial role of this drug class in different heart diseases. In vitro data implicated the activation of pro-survival pathways as a mechanism mediating the cardioprotective effects of calcium blockers (52). Treatment with verapamil improved the redox state in a model of ischemia-reperfusion injury.…”

“…Treatment with verapamil improved the redox state in a model of ischemia-reperfusion injury. Furthermore, verapamil induced the activation of Akt and ERK1/2 pathways, leading to a number of cardioprotective effects, such as the downregulation of apoptotic pathways (52). It was also proposed that this may be a mechanism by which calcium blockers amplify the ROS-induced damage, though a direct association between ROS and cardioprotective mechanisms of calcium channels blockers is not clearly demonstrated (52).…”

“…Furthermore, verapamil induced the activation of Akt and ERK1/2 pathways, leading to a number of cardioprotective effects, such as the downregulation of apoptotic pathways (52). It was also proposed that this may be a mechanism by which calcium blockers amplify the ROS-induced damage, though a direct association between ROS and cardioprotective mechanisms of calcium channels blockers is not clearly demonstrated (52). In addition, data indicate that amlodipine could have a beneficial effect on hypertension-induced cardiac hypertrophy by reducing the activity of NADPH oxidase (53).…”

Comparison of the -Adrenergic Receptor Antagonists Landiolol and Esmolol: Receptor Selectivity, Partial Agonism, and Pharmacochaperoning Actions

“…Although currently considered of major interest for drug development (Azzi et al, 2003;Kenakin, 2005;Whalen et al, 2011), the clinical significance of biased agonism is poorly understood. It is however clear that activation of ERK is cardioprotective during ischemia (Lips et al, 2004;Rose et al, 2010) and contributes to the cardioprotective actions of b-adrenergic antagonists (Kovacs et al, 2009).…”