Weizhong Zhu

Linkage of β1-adrenergic stimulation to apoptotic heart cell death through protein kinase A–independent activation of Ca2+/calmodulin kinase II

beta(1)-adrenergic receptor (beta(1)AR) stimulation activates the classic cAMP/protein kinase A (PKA) pathway to regulate vital cellular processes from the change of gene expression to the control of metabolism, muscle contraction, and cell apoptosis. Here we show that sustained beta(1)AR stimulation promotes cardiac myocyte apoptosis by activation of Ca(2+)/calmodulin kinase II (CaMKII), independently of PKA signaling. beta(1)AR-induced apoptosis is resistant to inhibition of PKA by a specific peptide inhibitor, PKI14-22, or an inactive cAMP analogue, Rp-8-CPT-cAMPS. In contrast, the beta(1)AR proapoptotic effect is associated with non-PKA-dependent increases in intracellular Ca(2+) and CaMKII activity. Blocking the L-type Ca(2+) channel, buffering intracellular Ca(2+), or inhibiting CaMKII activity fully protects cardiac myocytes against beta(1)AR-induced apoptosis, and overexpressing a cardiac CaMKII isoform, CaMKII-deltaC, markedly exaggerates the beta(1)AR apoptotic effect. These findings indicate that CaMKII constitutes a novel PKA-independent linkage of beta(1)AR stimulation to cardiomyocyte apoptosis that has been implicated in the overall process of chronic heart failure.

Protecting the myocardium: A role for the β2 adrenergic receptor in the heart

ObjectiveThe sympathetic nervous system enhances cardiac muscle function by activating &bgr; adrenergic receptors (&bgr;ARs). Recent studies suggest that chronic &bgr;AR stimulation is detrimental, however, and that it may play a role in the clinical deterioration of patients with congestive heart failure. To examine the impact of chronic &bgr;1AR and &bgr;2AR subtype stimulation individually, we studied the cardiovascular effects of catecholamine infusions in &bgr;AR subtype knockout mice (&bgr;1KO, &bgr;2KO). DesignProspective, randomized, experimental study. SettingAnimal research laboratory. Subjects&bgr;1KO and &bgr;2KO mice and wild-type controls. InterventionsThe animals were subjected to 2 wks of continuous infusion of the &bgr;AR agonist isoproterenol. Analyses of cardiac function and structure were performed during and 3 days after completion of the infusions. Functional studies included graded exercise treadmill testing, in vivo assessments of left ventricular function using Mikro-Tip catheter transducers, right ventricular pressure measurements, and analyses of organ weight to body weight ratios. Structural studies included heart weight measurements, assessments of myocyte ultrastructure using electron microscopy, and in situ terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling staining to quantitate myocyte apoptosis. Measurements and Main ResultsWe found that isoproterenol-treated &bgr;2KO mice experienced greater mortality rates (p = .001, chi-square test using Fisher’s exact method) and increased myocyte apoptosis at 3- and 7-day time points (p = .04 and p = .0007, respectively, two-way analysis of variance). ConclusionThe results of this study suggest that in vivo &bgr;2AR activation is antiapoptotic and contributes to myocardial protection.

β-Adrenergic Receptor–Mediated Cardiac Contractility Is Inhibited via Vasopressin Type 1A-Receptor–Dependent SignalingCLINICAL PERSPECTIVE

Background— Enhanced arginine vasopressin levels are associated with increased mortality during end-stage human heart failure, and cardiac arginine vasopressin type 1A receptor (V1AR) expression becomes increased. Additionally, mice with cardiac-restricted V1AR overexpression develop cardiomyopathy and decreased &bgr;-adrenergic receptor (&bgr;AR) responsiveness. This led us to hypothesize that V1AR signaling regulates &bgr;AR responsiveness and in doing so contributes to development of heart failure. Methods and Results— Transaortic constriction resulted in decreased cardiac function and &bgr;AR density and increased cardiac V1AR expression, effects reversed by a V1AR-selective antagonist. Molecularly, V1AR stimulation led to decreased &bgr;AR ligand affinity, as well as &bgr;AR-induced Ca2+ mobilization and cAMP generation in isolated adult cardiomyocytes, effects recapitulated via ex vivo Langendorff analysis. V1AR-mediated regulation of &bgr;AR responsiveness was demonstrated to occur in a previously unrecognized Gq protein–independent/G protein receptor kinase–dependent manner. Conclusions— This newly discovered relationship between cardiac V1AR and &bgr;AR may be informative for the treatment of patients with acute decompensated heart failure and elevated arginine vasopressin.