Beta3-Adrenergic Receptors in Cardiac and Vascular Tissues
Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium. Advances in pharmacology (San Diego, Calif.)
12/2010; 59:135-63. DOI: 10.1016/S1054-3589(10)59005-7
Catecholamines released by the orthosympathetic system play a major role in the short- and long-term regulation of cardiovascular function. Beta1- and beta2-adrenoreceptors (ARs) have classically been considered as mediating most of their effects on cardiac contraction. After their initial cloning and pharmacologic characterization in the late 1980s, beta3-ARs have been mostly thought of as receptors mediating metabolic effects (e.g., lipolysis) in adipocytes. However, definitive evidence for their expression and functional coupling in cardiovascular tissues (including in humans) has recently initiated a re-examination of their implication in the pathophysiology of cardiovascular diseases. Distinctive pharmacodynamic properties of beta3-AR, e.g., their upregulation in disease and resistance to desensitization, suggest that they may be attractive targets for therapeutic intervention. They may substitute efficient vasodilating pathways when beta1/2-ARs are inoperative. In the heart, their contractile effects, which are functionally antipathetic to those of beta1/2-AR, may protect the myocardium against adverse effects of excessive catecholamine stimulation and perhaps mediate additional ancillary effects on key aspects of electrophysiology or remodeling. Longitudinal studies in animals and patients with different stages of heart failure are now needed to identify the optimal therapeutic scheme using specific combinations of agonists or antagonists at all three beta-ARs.
Available from: PubMed Central
- "Thus, adrenergic receptors are important regulators of cardiovascular physiology. Although all three beta adrenergic receptor (β-AR) subtypes, β1, β2, and β3, are found in vascular smooth muscle cells, the β2-AR subtype is by far the most highly expressed . Of specific relevance to this paper is that the vascular β2-AR exhibits an age-related decline in signaling with advancing age that leads to impaired vasorelaxation. "
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ABSTRACT: Hypertension, orthostatic hypotension, arterial insufficiency, and atherosclerosis are common disorders in the elderly that lead to significant morbidity and mortality. One common factor to these conditions is an age-related decline in vascular beta-adrenergic receptor-mediated function and subsequent cAMP generation. Presently, there is no single cellular factor that can explain this age-related decline, and thus, the primary cause of this homeostatic imbalance is yet to be identified. However, the etiology is clearly associated with an age-related change in the ability of beta-adrenergic receptor to respond to agonist at the cellular level in the vasculature. This paper will review what is presently understood regarding the molecular and biochemical basis of age-impaired beta-adrenergic receptor-mediated signaling. A fundamental understanding of why β-AR-mediated vasorelaxation is impaired with age will provide new insights and innovative strategies for the management of multiple clinical disorders.
01/2012; 2012(2090-0384):915057. DOI:10.1155/2012/915057
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ABSTRACT: H9c2 cells are used as a surrogate for cardiac cells in several toxicological studies, which are usually performed with cells in their undifferentiated state, raising questions on the applicability of the results to adult cardiomyocytes. Since H9c2 myoblasts have the capacity to differentiate into skeletal and cardiac muscle cells under different conditions, the hypothesis of the present work was that cells in different differentiation states differ in their susceptibility to toxicants. In order to test the hypothesis, the effects of the cardiotoxicant isoproterenol (ISO) were investigated. The present work demonstrates that differentiated H9c2 cells are more susceptible to ISO toxicity. Cellular content of beta(1)-adrenergic receptors (AR), beta(3)-AR, and calcineurin is decreased as cells differentiate, as opposed to the content on the mitochondrial voltage-dependent anion channel (VDAC) and phosphorylated p38-MAPK, which increase. After ISO treatment, the pro-apoptotic protein Bax increases in all experimental groups, although only undifferentiated myoblasts up-regulate the anti-apoptotic Bcl-2. Calcineurin is decreased in differentiated H9c2 cells, which suggests an important role against ISO-induced cell death. The results indicate that the differentiation state of H9c2 myoblasts influence ISO toxicity, which may involve calcineurin, p38-MAPK, and Bax/Bcl-2 alterations. The data also provide new insights into cardiovascular toxicology during early development.
Cardiovascular toxicology 03/2011; 11(3):191-203. DOI:10.1007/s12012-011-9111-5 · 1.72 Impact Factor
Available from: Bertrand Rozec
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ABSTRACT: Catecholamines play a key role in the regulation of cardiovascular function, classically through ß(1/2)-adrenoreceptors (AR) activation. After ß(3)-AR cloning in the late 1980s, convincing evidence for ß(3)-AR expression and function in cardiovascular tissues recently initiated a reexamination of their involvement in the pathophysiology of cardiovascular diseases. Their upregulation in diseased cardiovascular tissues and resistance to desensitization suggest they may be attractive therapeutic targets. They may substitute for inoperant ß(1/2)-AR to mediate vasodilation in diabetic or atherosclerotic vessels. In cardiac ventricle, their contractile effects are functionally antipathetic to those of ß(1/2)-AR; in normal heart, ß(3)-ARs may mediate a moderate negative inotropic effect, but in heart failure, it may protect against adverse effects of excessive catecholamine stimulation by action on excitation-contraction coupling, electrophysiology, or remodelling. Thus, prospective studies in animals and patients at different stages of heart failure should lead to identify the best therapeutic window to use ß(3)-AR agonists and/or antagonists.
Current Heart Failure Reports 06/2011; 8(3):184-92. DOI:10.1007/s11897-011-0064-6
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