title: Beta1-adrenergic receptors stimulate cardiac contractility and CaMKII activation in vivo and enhance cardiac dysfunction following myocardial infarction.
abstract: The beta-adrenergic receptor (betaAR) 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 betaAR stimulation in augmenting cardiac function and its role in the activation of Ca(2+)/calmodulin-dependent kinase II (CaMKII) using various betaAR knockouts (KO) including beta(1)ARKO, beta(2)ARKO, and beta(1)/beta(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 betaAR 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 beta(1)ARKO and DKO compared with either the beta(2)ARKO or wild-type (WT) mice, indicating that beta(1)ARs are required for catecholamine-induced increases in contractility and CaMKII activity. Eight weeks after myocardial infarction (MI), beta(1)ARKO and DKO mice showed a significant attenuation in fractional shortening compared with either the beta(2)ARKO or WT mice. CaMKII activity after MI was significantly increased only in the beta(2)ARKO and WT hearts and not in the beta(1)ARKO and DKO hearts. The border zone of the infarct in the beta(2)ARKO and WT hearts demonstrated significantly increased apoptosis by TUNEL staining compared with the beta(1)ARKO and DKO hearts. Taken together, these data show that cardiac function and CaMKII activity are mediated almost exclusively by the beta(1)AR. Moreover, it appears that beta(1)AR signaling is detrimental to cardiac function following MI, possibly through activation of CaMKII.
authors.affiliation: Departments of Medicine, Cell Biology and Molecular Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: ByungSu
authors.initials: B
authors.lastname: Yoo
authors.forename: Anthony
authors.initials: A
authors.lastname: Lemaire
authors.forename: Supachoke
authors.initials: S
authors.lastname: Mangmool
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wolf
authors.forename: Antonio
authors.initials: A
authors.lastname: Curcio
authors.forename: Lan
authors.initials: L
authors.lastname: Mao
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006339:Heart Rate; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018342:Receptors, Adrenergic, beta-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013318:Stroke Volume; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D017725:Ventricular Pressure
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D000318:Adrenergic beta-Agonists; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007545:Isoproterenol