Selective β ₂ -Adrenoreceptor Stimulation Attenuates Myocardial Cell Death and Preserves Cardiac Function After Ischemia–Reperfusion Injury

Abstract

Objective β2-adrenoreceptor activation has been shown to protect cardiac myocytes from cell death. We hypothesized that acute β2-adrenoreceptor stimulation, using arformoterol (ARF), would attenuate myocardial ischemia/reperfusion (R) injury via NO synthase activation and cause a subsequent increase in NO bioavailability. Methods and Results Male C57BL/6J and endothelial NO synthase (eNOS) knockout mice were subjected to 45 minutes of myocardial ischemia and 24 hours of R. ARF or vehicle was administered 5 minutes before R. Serum troponin-I was measured, and infarct size per area-at-risk was evaluated at 24 hours of R. Echocardiography was performed at baseline and 2 weeks after R. Myocardial cAMP, protein kinase A, eNOS/Akt phosphorylation status, and NO metabolite levels were assayed. ARF (1 μg/kg) reduced infarct size per area-at-risk by 53.1% (P<0.001 versus vehicle) and significantly reduced troponin-I levels (P<0.001 versus vehicle). Ejection fraction was significantly preserved in ARF-treated hearts compared with vehicle hearts at 2 weeks of R. Serum cAMP and nuclear protein kinase A C-α increased 5 and 15 minutes after ARF injection, respectively (P<0.01). ARF increased Akt phosphorylation at Thr308 (P<0.001) and Ser473 (P<0.01), and eNOS phosphorylation at Ser1177 (P<0.01). ARF treatment increased heart nitrosothiol levels (P<0.001) at 15 min after injection. ARF failed to reduce infarct size in eNOS−/− mice. Conclusions Our results indicate that β2-adrenoreceptor stimulation activates cAMP, protein kinase A, Akt, and eNOS and augments NO bioavailability. Activation of this prosurvival signaling pathway attenuates myocardial cell death and preserves cardiac function after ischemia/reperfusion.

Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection

“…For example, M␤CD consistently inhibits BK Ca channel function across different cell types, and the channel has been implicated in cytoprotection and I/R injury. Similarly, ␤ 2 -AR function is consistently perturbed by cholesterol depletion, and these receptors are also cardioprotective (5,9). Nonetheless, the present study contrasts with those of Das et al (8) and Sun et al (53), in which no changes in I/R tolerance (or normoxic function) were observed after M␤CD treatment.…”

Role of β-Adrenergic Receptors and Nitric Oxide Signaling in Exercise-Mediated Cardioprotection

“…Recent experimental evidence demonstrates that stimulation of ␤ 2 -ARs activates eNOS via a Src kinase-PI3K/ Akt-dependent but cAMP/PKA-, MAPK-, and AMPKindependent pathway (2). Additionally, activation of the ␤ 2 -AR promotes eNOS activation, increased NO metabolites, and myocardial protection following I/R in mice (4). However, the precise role or potential mechanism by which ␤ 2 -AR activation mediates exercise-induced cardioprotection has not been investigated.…”

Mechanisms Responsible for the Trophic Effect of Beta-Adrenoceptors on the ItoCurrent Density in Type 1 Diabetic Rat Cardiomyocytes

“…β 1 is the most abundant beta subtype in the heart, but β2 is not less physiologically relevant as it can, for instance, protect cardiac myocytes from cell death after ischemia and reperfusion injury [25]. Although they differ in physiological roles and pharmacological properties, both activate the classic Gαs-AC-cAMP-PKA pathway, whereas only β2 activates also Gαi protein [reviewed in [26]].…”