Genetically changed mice with chronic deficiency or overexpression of the β-adrenoceptors—what can we learn for the therapy of heart failure?

Abstract

Heart failure is one of the most common medical diseases-almost every third 55-year-old person in the Western world is going to develop heart failure in his or her life. The development of heart failure is associated with pivotal restructuring of the beta-adrenergic system. The beta-adrenoceptor antagonists have emerged to be an essential part of the therapy of chronic heart failure. Three different beta-adrenoceptors could be identified and characterized so far. The beta1-adrenoceptors are being down-regulated, while the beta3-adrenoceptors are being up-regulated. The mechanisms that are responsible for the positive impact of beta-adrenoceptor antagonists are not completely understood up to now. Therefore, it is necessary to point out the crucial role of the beta-adrenergic system for the regulation of the cardiovascular system and the pathogenesis of heart failure. In the recent couple of years, numerous transgenic mouse models have proven to be helpful to gain a better understanding of the function and the relevance of these receptors. This review gives an overview of the pathophysiological relevance of the beta-adrenergic system for heart failure and outlines the most important insights concerning heart function, which could be derived from genetically changed mice with chronic deficiency and overexpression of the beta-adrenoceptor.

β-Blockers, heart disease and COPD: current controversies and uncertainties

“…Animal studies have suggested that long-term activation of β1-adrenoceptors has more marked deleterious effects than activation of β2-adrenoceptors,36 and the beneficial effects of β-blockers are therefore attributed to β1-blockade 16…”

Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling

“…There is also evidence that long-term activation of β 1 -adrenoceptors in animals has more deleterious effects than activation of β 2 -adrenoceptors. Transgenic mice with modest overexpression of β 1 -adrenoceptors rapidly develop cardiac failure and die, whereas β 2 -adrenoceptor overexpression is better tolerated [30]. In humans, use of β 1 -adrenoceptor-selective agonists was associated with an increase in mortality [31] and they are now restricted to short-term maintenance of cardiac output in intensive and coronary care units.…”

β-Adrenergic stimulation and myocardial function in the failing heart

“…Later in life, however, overexpression of b 1 -AR, b 2 -AR (at high density, differences between b 1 -and b 2 -AR overexpressors are discussed in depth in Refs. [53,102]), G as , or PKA causes cardiomyopathy and/or arrhythmia, and premature death [103][104][105][106][107]. b 2 -AR overexpression, despite augmenting cardiac output under normal unstressed conditions, was accompanied by exaggerated myocardial damage after ischemia-reperfusion injury or pressure overload [108,109].…”

“…Apart from the b 1 -and b 2 -adrenoceptor knockout mice (recently reviewed in depth [102]), two genetically engineered mice exist, in which stimulating components were deleted: AC5 [121] and phosphatase I-1 [122]. Mice with targeted ablation of AC5 have a normal cardiac phenotype, but were protected from heart failure after pressure overload or long-term b-adrenergic stimulation [123,124].…”