BETA1-ADRENERGIC RECEPTORS STIMULATE CARDIAC CONTRACTILITY AND CAMKII ACTIVATION IN VIVO AND ENHANCE CARDIAC DYSFUNCTION FOLLOWING MYOCARDIAL INFARCTION

The beta-adrenergic receptor signaling system is one of the most powerful regulators of cardiac function and a key regulator of Ca2+ homeostasis. We investigated the role of beta-AR stimulation in augmenting cardiac function and its role in the activation of Ca2+/calmodulin-dependent kinase II (CaMKII) using various beta-AR knockouts (KO) including beta1ARKO, beta2ARKO, and beta1/2AR double-KO (DKO) mice. We employed a murine model of left anterior descending coronary artery ligation to examine the differential contributions of specific beta-AR subtypes in the activation of CaMKII in vivo in failing myocardium. Cardiac inotropy, chronotropy, and CaMKII activity following short term isoproterenol stimulation were significantly attenuated in beta1ARKO and DKO compared with either the beta2ARKO or wild-type (WT) mice, indicating that beta1ARs are required for catecholamine-induced increases in contractility and CaMKII activity. Eight weeks after myocardial infarction (MI), beta1ARKO and DKO mice showed a significant attenuation in fractional shortening compared with either the beta2ARKO or WT mice. CaMKII activity after MI was significantly increased only in the beta2ARKO and WT hearts and not in the beta1ARKO and DKO hearts. The border zone of the infarct in the 2ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared with the 1ARKO and DKO hearts. Taken together, these data show that cardiac function and CaMKII activity are mediated almost exclusively by the beta1AR. Moreover, it appears that beta1AR signaling is detrimental to cardiac function following MI, possibly through activation of CaMKII.