β 1 -Adrenergic receptors stimulate cardiac contractility and CaMKII activation in vivo and enhance cardiac dysfunction following myocardial infarction
The β-adrenergic receptor (βAR) signaling system is one of the most powerful regulators of cardiac function and a key regulator of Ca 2+ homeostasis. We investigated the role of βAR stimulation in augmenting cardiac function and its role in the activation of Ca 2+ /calmodulin-dependent kinase II (CaMKII) using various βAR knockouts (KO) including β 1 ARKO, β 2 ARKO, and β 1 /β 2 AR double-KO (DKO) mice. We employed a murine model of left anterior descending coronary artery ligation to examine the differential contributions of specific βAR 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 β 1 ARKO and DKO compared with either the β 2 ARKO or wild-type (WT) mice, indicating that β 1 ARs are required for catecholamine-induced increases in contractility and CaMKII activity. Eight weeks after myocardial infarction (MI), β 1 ARKO and DKO mice showed a significant attenuation in fractional shortening compared with either the β 2 ARKO or WT mice. CaMKII activity after MI was significantly increased only in the β 2 ARKO and WT hearts and not in the β 1 ARKO and DKO hearts. The border zone of the infarct in the β 2 ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared with the β 1 ARKO and DKO hearts. Taken together, these data show that cardiac function and CaMKII activity are mediated almost exclusively by the β 1 AR. Moreover, it appears that β 1 AR signaling is detrimental to cardiac function following MI, possibly through activation of CaMKII. Copyright © 2009 the American Physiological Society.
Yoo, BS; Lemaire, A; Mangmool, S; Wolf, MJ; Curcio, A; Mao, L; Rockman, HA
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