The Developmental and Physiological Consequences of Disrupting Genes Encoding β1 and β2 Adrenoceptors

Rohrer, Daniel K.; Bernstein, Daniel; Chruscinski, Andrzej; Desai, Kavin; Schauble, Eric; Kobilka, Brian K.

doi:10.1016/s1054-3589(08)60798-x

Cited by 19 publications

(11 citation statements)

References 1 publication

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“…Similar to ␤1 knockouts, ␤1/␤2 double knockout mice were able to exercise to the same total workload as wild types, despite also having a blunted tachycardic response. However, in contrast to ␤1 knockouts, the double knockouts manifested decreased V O 2 and V CO 2 at all workloads (51).…”

Section: Review: Exercise Assessment Of Transgenic Modelsmentioning

confidence: 72%

Exercise assessment of transgenic models of human cardiovascular disease

Bernstein

2003

Physiological Genomics

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Bernstein, Daniel. Exercise assessment of transgenic models of human cardiovascular disease. Physiol Genomics 13: 217-226, 2003; 10.1152/ physiolgenomics.00188.2002.-Exercise provides one of the most severe, yet physiological, stresses to the intact cardiovascular system and is a major determinant of the utilization of metabolic substrates. The adaptations to exercise are the result of a coordinated response of multiple organ systems, including cardiovascular, pulmonary, endocrine-metabolic, immunologic, and skeletal muscle. With the proliferation of genetically altered murine models of cardiovascular disease, the importance of developing methods of accurate physiological phenotyping is critical. There are numerous examples of transgenic models in which the baseline cardiovascular phenotype is unchanged or minimally changed from the wild type, only to become manifest during the stress of exercise testing. In this review, we cover the basics of the murine cardiovascular response to exercise and the importance of attending to strain differences, compare different exercise methodologies (constant workload treadmill, incremental workload treadmill, swimming) and hemodynamic monitoring systems, and examine the murine response to exercise conditioning. Several examples where exercise studies have contributed to the elucidation of cardiovascular phenotypes are reviewed: the ␤-adrenergic receptor knockouts, phospholamban knockout, dystrophin knockout (mdx), and the mutant ␣-myosin heavy chain (R403Q) transgenic.␤-adrenergic receptor knockout; skeletal muscle; phospholamban knockout; dystrophin knockout; mutant ␣-myosin heavy chain transgenic OVER THE PAST DECADE, there has been a proliferation of genetically modified animal models of human cardiovascular disease. Despite adaptation of transgenic technology to larger mammals, the mouse remains the most commonly used species for transgenic studies and continues to be the only species in which targeted genetic deletions are possible. The addition of technologies allowing tissue-specific knockouts as well as the ability to turn gene expression on and off again at will enhances our ability to study genetic regulation of the cardiovascular system. Some phenotypes, however, may be extremely subtle. Thus thorough evaluation of genetically altered murine models requires the ability to study all components of murine cardiovascular physiology. The development of techniques allowing the evaluation of mice in an awake, unrestrained state has advanced the study of true resting cardiovascular dynamics and has also allowed the introduction of exercise testing to study cardiovascular response during stressed states. Exercise studies provide valuable information about how the cardiovascular system responds under maximally stimulated conditions, with the possibility of uncovering phenotypes not observed at rest. Given the expense and time involved in creating genetically altered murine models of human cardiovascular disease, it is not unreasonable to suggest that most if not all models s...

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Section: Review: Exercise Assessment Of Transgenic Modelsmentioning

confidence: 72%

Exercise assessment of transgenic models of human cardiovascular disease

Bernstein

2003

Physiological Genomics

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“…Differential activation of MAPK isoforms, previously shown in vitro to regulate ␤-agonist as well as doxorubicin cardiotoxicity, appears to play a role in mediating the differential effects of these ␤-adrenergic receptor subtypes in vivo. cardiomyopathy; anthracycline; adrenergic receptor; cell signaling; ␤-blocker; mitogen-activated protein kinase ␤-ADRENERGIC RECEPTORS (␤-ARs) are members of the superfamily of seven-transmembrane G protein-coupled receptors (30), three subtypes of which (␤1, ␤2, ␤3) have been identified in the heart (6,11,13,14,(25)(26)(27). Classically, ␤-ARs were regarded primarily as regulators of cardiac function (inotropy, lusitropy, and chronotropy).…”

mentioning

confidence: 99%

“…␤-ADRENERGIC RECEPTORS (␤-ARs) are members of the superfamily of seven-transmembrane G protein-coupled receptors (30), three subtypes of which (␤1, ␤2, ␤3) have been identified in the heart (6,11,13,14,(25)(26)(27). Classically, ␤-ARs were regarded primarily as regulators of cardiac function (inotropy, lusitropy, and chronotropy).…”

mentioning

confidence: 99%

Differential cardioprotective/cardiotoxic effects mediated by β-adrenergic receptor subtypes

Bernstein¹,

Fajardo²,

Zhao³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Recent data suggest that beta-adrenergic receptor subtypes couple differentially to signaling pathways regulating cardiac function vs. cardiac remodeling. To dissect the roles of beta1- vs. beta2-receptors in the pathogenesis of cardiomyopathy, doxorubicin was administered to beta1, beta2, and beta1/beta2 knockout (-/-) and wild-type mice. Expression and activation of MAPKs were measured. Wild-type and beta1-/- mice showed no acute cardiovascular effects, whereas beta2-/- mice all died within 30 min. The additional deletion of the beta1-receptor (beta1/beta2-/-) totally rescued this toxicity. beta2-/- mice developed decreased contractile function, hypotension, QTc prolongation, and ST segment changes and a 20-fold increase in p38 MAPK activity not seen in the other genotypes. The MAPK inhibitor SB-203580 rescued beta2-/- mice from this acute toxicity. The enhanced toxicity in beta2-/- mice was also recapitulated in wild-type mice with the beta2-selective antagonist ICI-118,551, although the rescue effect of the beta1-deletion was not recapitulated using the beta1-selective antagonist metoprolol or the nonselective beta-antagonist propranolol. These data suggest that beta2-adrenergic receptors play a cardioprotective role in the pathogenesis of cardiomyopathy, whereas beta1-adrenergic receptors mediate at least some of the acute cardiotoxicity of anthracyclines. Differential activation of MAPK isoforms, previously shown in vitro to regulate beta-agonist as well as doxorubicin cardiotoxicity, appears to play a role in mediating the differential effects of these beta-adrenergic receptor subtypes in vivo.

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“…Both genes exist in the C18QTL3-lodging interval (Supplement 3, http://links.lww.com/HJH/A490). Knocking out either Adrb2 [32] or Nedd4l [33] alters BP. Physiologically, they appeared the ideal candidates for C18QTL3.…”

Section: Mechanistic Connection To Blood Pressure Regulationmentioning

confidence: 99%

Two candidate genes for two quantitative trait loci epistatically attenuate hypertension in a novel pathway

Chauvet

Ménard²,

Deng³

2015

Journal of Hypertension

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The pathway initiated by Hdhd2/C18QTL4 upstream of Tcof1/C18QTL3 reveals novel mechanistic insights into BP modulations. Their discovery might yield innovative therapeutic targets and diagnostic tools predicated on a novel BP cause and mechanism that is determined by a regulatory hierarchy. Optimizing the de-phosphorylation capability and its downstream target could be antihypertensive. The conceptual paradigm of an order and regulatory hierarchy may help unravel genetic and molecular relationships among certain human BP QTLs.

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The Developmental and Physiological Consequences of Disrupting Genes Encoding β1 and β2 Adrenoceptors

Cited by 19 publications

References 1 publication

Exercise assessment of transgenic models of human cardiovascular disease

Exercise assessment of transgenic models of human cardiovascular disease

Differential cardioprotective/cardiotoxic effects mediated by β-adrenergic receptor subtypes

Two candidate genes for two quantitative trait loci epistatically attenuate hypertension in a novel pathway

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