Higenamine protects ischemia/reperfusion induced cardiac injury and myocyte apoptosis through activation of β2-AR/PI3K/AKT signaling pathway

Abstract

Cardiomyocyte apoptosis contributes to ischemic cardiac injury and the development of heart failure. Higenamine is a key component of the Chinese herb aconite root that has been prescribed for treating symptoms of heart failure for thousands of years in the oriental Asian countries. It has been shown that higenamine has anti-apoptotic effects in a few cell types including cardiomyocytes. However, the pharmacological target and molecular mechanism of higenamine in the heart are still not fully illustrated. Herein, we report that higenamine protected myocyte apoptosis and ischemia/reperfusion (I/R) injury through selective activation of beta2-adrenergic receptor (β2-AR). In particular, we show that higenamine significantly reduced I/R-induced myocardial infarction in mice. In both primary neonatal rat and adult mouse ventricular myocytes, we show higenamine inhibited cell apoptosis and also reduced biochemical markers of apoptosis such as cleaved caspase 3 and 9. More importantly, we show that the anti-apoptotic effects of higenamine in cardiomyocytes were completely abolished by β2-AR but not β1-AR antagonism. Furthermore, we confirmed that higenamine attenuated I/R-induced myocardial injury and reduced cleaved caspases in a β2-AR dependent manner in intact mouse hearts. Higenamine stimulated AKT phosphorylation and required PI3K activation for the anti-apoptotic effect in cardiomyocytes. These findings together suggest that anti-apoptotic and cardiac protective effects of higenamine are mediated by the β2-AR/PI3K/AKT cascade.

Insulin and β Adrenergic Receptor Signaling: Crosstalk in Heart

“…Meanwhile, an upregulation of G i is often associated with enhanced β 2 AR-Gi signaling in HF. The enhanced β 2 AR-G i signaling leading to Akt activation can protect against myocyte apoptosis, and consequently slow down the progression of cardiomyopathy [26]. Therefore, a combined therapy of β 1 AR blocker and β 2 AR agonist has been proposed for treatment of HF.…”

A minimally invasive approach to induce myocardial infarction in mice without thoracotomy

“…Studies have also demonstrated an important role of apoptosis in ischaemic heart disease, contributing to myocyte cell death in MI and left ventricular remodelling . To examine whether this model is applicable to study cardiac myocyte apoptosis induced by MI, we detected the apoptosis by TUNEL.…”

“…Studies have also demonstrated an important role of apoptosis in ischaemic heart disease, contributing to myocyte cell death in MI and left ventricular remodelling. 27 To examine whether this model is applicable to study cardiac myocyte apoptosis induced by MI, we detected the apoptosis by TUNEL. As shown in Figure 6B, the apoptosis rate of cardiac myocyte in ischaemic area was completely increased in mice with the surgeries of both traditional method and new method, compared to sham mice.…”

Vinpocetine Attenuates Pathological Cardiac Remodeling by Inhibiting Cardiac Hypertrophy and Fibrosis

“…Adult mouse cardiomyocytes were isolated from hearts of C57BL/6J mice by enzymatic dissociation using collagenase type II in a Langerdorff perfusion system, according to a previously described protocol with modification [14]. In brief, heparinized and anesthetized mouse heart were rapidly excised, cannulated, and perfused with Ca 2+ free isolation buffer (120 mM NaCl, 15 mM KCl, 0.6 mM KH 2 PO 4 , 0.6 mM Na 2 HPO 4 , 4.6 mM NaHCO 3 , 1.2 mM MgSO 4 , 10 mM HEPES, 30 mM taurine, 5.5 mM glucose, 10 mM 2,3-butanedione monoxime (BDM), 10 mM creatine monohydrate, pH 7.4) for 3 min followed by collagenase type II (Worthington) mixed isolation buffer (50 mg in 50 mL isolation buffer, 40 nM CaCl 2 ) until digestion was complete.…”