β-Adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic Gsα mouse

Asai, Kuniya; Yang, Gui Ping; Geng, Yong; Takagi, Gen; Bishop, Sanford P.; Ishikawa, Yoshihiro; Shannon, Richard P.; Wagner, Thomas E.; Vatner, Dorothy E.; Homcy, Charles J.; Vatner, Stephen F.

doi:10.1172/jci7418

Cited by 121 publications

(90 citation statements)

References 41 publications

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“…The notion that increased G s signaling can lead to apoptosis is further supported by studies demonstrating that heart failure and apoptosis develop in older transgenic mice overexpressing the alpha subunit of G s in the myocardium . When activation of endogenous b-AdrR in Gas transgenic mice was blocked with propranolol, cardiomyocyte apoptosis and cardiac dysfunction were prevented (Akai et al, 1999). These studies suggest that chronic sympathetic stimulation over an extended period of time can contribute to the development of apoptotic heart failure.…”

Section: Gas Signaling In Apoptosis and Failurementioning

confidence: 81%

G-proteins in growth and apoptosis: lessons from the heart

2001

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The acute contractile function of the heart is controlled by the e ects of released nonepinephrine (NE) on cardiac adrenergic receptors. NE can also act in a more chronic fashion to induce cardiomyocyte growth, characterized by cell enlargement (hypertrophy), increased protein synthesis, alterations in gene expression and addition of sarcomeres. These responses enhance cardiomyocyte contractile function and thus allow the heart to compensate for increased stress. The hypertrophic e ects of NE are mediated through Gq-coupled a 1 -adrenergic receptors and are mimicked by the actions of other neurohormones (endothelin, prostaglandin F 2a angiotensin II) that also act on Gq-coupled receptors. Activation of phospholipase C by Gq is necessary for these responses, and protein kinase C and MAP kinases have also been implicated. Gq stimulated cardiac hypertrophy is also evident in transgenic mouse models. In contrast, stimulation of G s -coupled b-adrenergic receptors or G i -coupled receptors do not directly e ect cardiomyocyte hypertrophy. Apoptosis is also induced by G-protein-coupled receptor stimulation in cardiomyocytes. Sustained or excessive activation of either Gq-or Gs-signaling pathways results in apoptotic loss of cardiomyocytes both in vitro and in vivo. Apoptosis is associated with decreased ventricular function in the failing heart. Cardiomyocytes provide an ideal model system for understanding the basis for G-protein mediated hypertrophy and apoptosis, and the mechanisms responsible for the transition from compensatory to deleterious levels of signaling. This information may prove critical for designing interventions that prevent the pathophysiological consequences of heart failure. Oncogene (2001) 20, 1626 ± 1634.

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Section: Gas Signaling In Apoptosis and Failurementioning

confidence: 81%

G-proteins in growth and apoptosis: lessons from the heart

2001

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“…Echocardiography was performed by using ultrasonography (Sequoia C256; Acuson, Malvern, PA; refs. [12][13][14]. A dynamically focused 13-MHz annular array transducer was applied from below, by using a warmed saline bag as a standoff.…”

Section: Methodsmentioning

confidence: 99%

“…DNA fragmentation was detected in situ by using terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining (14). Briefly, deparaffinized sections were incubated with proteinase K and DNA fragments labeled with biotin-conjugated dUTP and terminal deoxyribonucleotide transferase and visualized with FITCExtrAvidin (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies suggest that ␤-AR blockade, rather than stimulation, is beneficial in patients with heart failure (5-7). Most prior experimental studies on this topic have focused on mouse models overexpressing ␤-AR (8-11), Gs␣ (12)(13)(14), or protein kinase A (PKA) (15), and the results from these studies support the use of ␤-AR blockade in heart failure, because these genetically engineered mouse models demonstrated that prolonged ␤-AR stimulation results in cardiomyopathy and that the adverse effects of pressure overload are exacerbated (11). Interestingly, the results from genetically engineered mouse models in which isoforms of adenylyl cyclase (AC) have been overexpressed are at variance with the above results (16)(17)(18)(19)(20)(21)(22).…”

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confidence: 99%

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Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload

Okumura¹,

Takagi²,

Kawabe³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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185

164

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The sympathetic nervous system is designed to respond to stress. Adenylyl cyclase (AC) is the keystone of sympathetic transmission, yet its role in response to acute overload in the heart or in the pathogenesis of heart failure is controversial. We examined the effects of pressure overload, induced by thoracic aortic banding, in mice in which type 5 AC, a major cardiac AC isoform, was disrupted (AC5 ؊/؊ ). Left ventricular weight͞tibial length ratio (LVW͞TL) was not different between the WT and AC5 ؊/؊ at baseline and increased progressively and similarly in both groups at 1 and 3 wk after aortic banding. However, LV ejection fraction (LVEF) fell in WT at 3 wk after banding (from 70 ؎ 2.8 to 57 ؎ 3.9%, P < 0.05), and this decrease was associated with LV dilatation, indicating incipient cardiac failure. In contrast, AC5 ؊/؊ mice did not exhibit a fall in LVEF from 74 ؎ 2.2%. The number of apoptotic myocytes was similar at baseline, but it increased roughly 4-fold in WT at both 1 and 3 wk after banding, and significantly less, P < 0.05, in AC5 ؊/؊ . Importantly, the increase in apoptosis occurred before the decline in LVEF in WT. The protective mechanism seems to involve Bcl-2, which was up-regulated significantly more in AC5 ؊/؊ mice with pressure overload. Our findings suggest that limiting type 5 AC plays a protective role in response to pressure overload and the development of heart failure, potentially through limiting the incidence of myocardial apoptosis.

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“…All rats were treated for 24 weeks to ensure a sufficient timewindow for LV remodeling and therapeutic effects to take place. 6 As the purpose of this study was to compare the efficacy of different AR antagonists in suppressing LV remodeling secondary to hypertension, the prerequisite for a chosen drug is to lower blood pressure to a normal level. The drug doses were determined by referring to previous studies on animal models of LV remodeling [7][8][9][10] and by a preliminary study in which the drug doses were increased gradually from a low dose until the systolic blood pressure (SBP) in each drug-treated group reached the level of SBP as that of WKY rats.…”

Section: Animal Model and Experimental Protocolmentioning

confidence: 99%

Is overall blockade superior to selective blockade of adrenergic receptor subtypes in suppressing left ventricular remodeling in spontaneously hypertensive rats?

et al. 2010

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To test the hypothesis that nonselective blockade of adrenergic receptor (AR) subtypes is superior to selective blockade of AR subtypes in suppressing left ventricular (LV) remodeling induced by hypertension. Sixty-four spontaneously hypertensive rats (SHR) were randomly divided into four groups: bisoprolol-treated, propranolol-treated, carvedilol-treated and no treatment groups (n¼16, each). Sixteen Wistar-Kyoto (WKY) rats served as a control group. Echocardiography and cardiac catheterization were carried out to record the mitral flow velocity ratio of E wave to A wave (E/A), LV mass index (LVMI), maximal rising (dp/dt max ) and falling (Àdp/dt max ) rate of the LV pressure and LV relaxation time constant (s). The mRNA and protein expression levels of AR, protein kinase(PK) and G-protein subtypes, intracellular free calcium (Ca 2+ ) concentration and cardiocyte apoptoisis rate were determined. Three drug-treated groups showed higher velocity ratio of E wave to A wave (E/A) and Àdp/dt max and lower systolic blood pressure (SBP), LVMI, s, apoptosis rate and intracellular free Ca 2+ concentration than the no treatment group. The mRNA expression levels of AR-a 1B in the carvedilol group were significantly lower than the other two drug-treated groups. The mRNA expression levels of AR-b 1 , AR-b 2 and Gsa were significantly higher in the three drug-treated groups than in the no treatment group, with the expression levels of AR-b 2 being the highest in the carvedilol-treated group. The protein expression levels of PKA and PKC subtype a and d were lower in the three drug-treated groups than in the no treatment group. Overall blockade of AR subtypes is not superior to selective blockade of AR subtypes in suppressing LV remodeling in SHR. Although carvedilol is the most effective in attenuating cardiocyte apoptosis, normalizing AR-a 1B and Gsa expression and increasing AR-b 2 expression.

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β-Adrenergic receptor blockade arrests myocyte damage and preserves cardiac function in the transgenic Gsα mouse

Cited by 121 publications

References 41 publications

G-proteins in growth and apoptosis: lessons from the heart

G-proteins in growth and apoptosis: lessons from the heart

Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload

Is overall blockade superior to selective blockade of adrenergic receptor subtypes in suppressing left ventricular remodeling in spontaneously hypertensive rats?

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