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This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/H1377    most recent 00504.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Yoo, B. Articles by Rockman, H. A. PubMed PubMed Citation Articles by Yoo, B. Articles by Rockman, H. A.

β₁-Adrenergic receptors stimulate cardiac contractility and CaMKII activation in vivo and enhance cardiac dysfunction following myocardial infarction

Departments of Medicine, Cell Biology and Molecular Genetics, Duke University Medical Center, Durham, North Carolina

Submitted June 3, 2009 ; accepted in final form July 20, 2009

The β-adrenergic receptor (βAR) signaling system is one of the most powerful regulators of cardiac function and a key regulator of Ca²⁺ homeostasis. We investigated the role of βAR stimulation in augmenting cardiac function and its role in the activation of Ca²⁺/calmodulin-dependent kinase II (CaMKII) using various βAR knockouts (KO) including β₁ARKO, β₂ARKO, and β₁/β₂AR 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 β₁ARKO and DKO compared with either the β₂ARKO or wild-type (WT) mice, indicating that β₁ARs are required for catecholamine-induced increases in contractility and CaMKII activity. Eight weeks after myocardial infarction (MI), β₁ARKO and DKO mice showed a significant attenuation in fractional shortening compared with either the β₂ARKO or WT mice. CaMKII activity after MI was significantly increased only in the β₂ARKO and WT hearts and not in the β₁ARKO and DKO hearts. The border zone of the infarct in the β₂ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared with the β₁ARKO and DKO hearts. Taken together, these data show that cardiac function and CaMKII activity are mediated almost exclusively by the β₁AR. Moreover, it appears that β₁AR signaling is detrimental to cardiac function following MI, possibly through activation of CaMKII.

Ca²⁺/calmodulin-dependent kinase II; heart failure; apoptosis; knockout mice; pressure-volume relations