Recent Advances in Cardiac β
            <sub>2</sub>
            -Adrenergic Signal Transduction

Xiao, Rui‐Ping; Cheng, Heping; Zhou, Yingying; Kuschel, Meike; Lakatta, Edward G.

doi:10.1161/01.res.85.11.1092

Cited by 223 publications

(176 citation statements)

References 84 publications

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“…Inherent in the clinical discussion is recent molecular insight into differences between cardiac ␤ 1 -and ␤ 2 -adrenoreceptor stimulation at the signal-transduction level (10,11). In rat cardiomyocytes, a ␤ 2 -agonist, zinterol, was shown to increase calcium current in a manner qualitatively distinct from ␤ 1 -adrenoreceptor stimulation (12), consistent with single-channel effects reported later (13).…”

supporting

confidence: 61%

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Foerster

Groner

Matthes

et al. 2003

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

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Two subtypes of ␤-adrenoceptors, ␤1 and ␤2, mediate cardiac catecholamine effects. These two types differ qualitatively, e.g., regarding G protein coupling and calcium channel stimulation. Transgenic mice overexpressing human ␤2-adrenoceptors survive high-expression levels, unlike mice overexpressing ␤1-adrenoceptors. We examined the role of inhibitory Gi proteins, known to be activated by ␤2-but not ␤1-adrenoceptors, on the chronic effects of human ␤2-adrenoreceptor overexpression in transgenic mice. These mice were crossbred with mice where G␣i2, a functionally important cardiac Gi ␣-subunit, was inactivated by targeted gene deletion. Survival of ␤2-adrenoreceptor transgenic mice was reduced by heterozygous inactivation of G␣i2. Homozygous knockout͞␤2-adrenoreceptor transgenic mice died within 4 days after birth. Heterozygous knockout͞␤2-adrenoreceptor transgenic mice developed more pronounced cardiac hypertrophy and earlier heart failure compared with ␤2-adrenoreceptor transgenic mice. Single calcium-channel activity was strongly suppressed in heterozygous knockout͞␤2-adrenoreceptor transgenic mice. In cardiomyocytes from these mice, pertussis toxin treatment in vitro fully restored channel activity and enhanced channel activity in cells from homozygous G␣i2 knockout animals. Cardiac G␣i3 protein was increased in all G␣i2 knockout mouse strains. Our results demonstrate that G␣i2 takes an essential protective part in chronic signaling of overexpressed ␤2-adrenoceptors, leading to prolonged survival and delayed cardiac pathology. However, reduction of calcium-channel activity by ␤2-adrenoreceptor overexpression is due to a different pertussis-toxin-sensitive pathway, most likely by G␣i3. This result indicates that subtype-specific signaling of ␤2-adrenoreceptor functionally bifurcates at the level of Gi, leading to different effects depending on the G␣ isoform.L-type calcium channel ͉ single channel recording ͉ mouse genetics ͉ survival curve ͉ pertussis toxin C ardiac stimulatory catecholamine effects are mediated by both ␤ 1 -and ␤ 2 -adrenergic receptors (␤-adrenoceptors), mainly through cAMP-dependent protein kinase A-catalyzed phosphorylation of cardiac proteins involved in calcium homeostasis, such as phospholamban and the L-type calcium channel. Evidently, this pathway is compromised in heart failure. Because of the clear-cut evidence that ␤ 2 -adrenoceptors mediate acute functional effects in human cardiomyocyte in vitro (1, 2) and in vivo (3), a rationale for ␤ 2 -adrenoreceptor gene therapy exists (4-6). Whether and where ␤ 2 -adrenoreceptor stimulation or inhibition, by pharmacological or genetic means, will have its place in heart failure therapy is an open question (7-9).Inherent in the clinical discussion is recent molecular insight into differences between cardiac ␤ 1 -and ␤ 2 -adrenoreceptor stimulation at the signal-transduction level (10, 11). In rat cardiomyocytes, a ␤ 2 -agonist, zinterol, was shown to increase calcium current in a manner qualitatively distinct from ␤ 1 -adrenoreceptor stimu...

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supporting

confidence: 61%

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Foerster

Groner

Matthes

et al. 2003

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

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“…30,31,33,37 Recent studies in rodent cardiomyocytes revealed that b 2 -receptors couple to G-proteins, which lead to inhibition of cyclic AMP formation downstream. 38,39 In the ischaemic myocardium, the Na + /H + exchanger, which itself is under the influence of the C825T polymorphism, 3,4 exerts an important modulatory action on cardiac excitation-contraction coupling. 36 Published studies on the possible influence of the GNB3 C825T polymorphism reported inconsistent results.…”

Section: Discussionmentioning

confidence: 99%

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

et al. 2003

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The 825T allele of the G-protein b 3 -subunit is associated with increased intracellular signalling. Its association with hypertension is inconsistent. We, therefore, studied the C825T polymorphism in relation to ambulatory blood pressure as well as left ventricular structure and function in two European populations. We genotyped 248 parents and 318 offspring, enrolled in the European Project on Genes in Hypertension in Cracow, Poland (n ¼ 286) and in Novosibirsk, Russian Federation (n ¼ 280). The 24-h ambulatory blood pressure was recorded using oscillometric SpaceLabs 90207 monitors. Within each centre, a single observer performed two-dimensionally guided M-mode echocardiography and Doppler sonography to measure left ventricular structure (American Society of Echocardiography conventions) and diastolic function: early (E) and late (A) peak diastolic inflow velocities. We used analysis of covariance and generalized estimating equations to allow for covariables and nonindependence among related subjects. Genotype frequencies were similar (P ¼ 0.25) in Cracow and Novosibirsk and amounted to 44.7% for CC, 47.2% for CT, and 8.1% for TT. Among parents (mean age: 51.3 years)Fbut not among offspring (mean age 25.1 years)F24-h, daytime and night time systolic blood pressures were 5-6 mmHg higher in TT homozygotes than in C allele carriers. In TT homozygous parents (À8.2 cm/sec, P ¼ 0.004) as well as in TT homozygous offspring (À7.5 cm/sec, P ¼ 0.02), the E-wave was significantly reduced, which in offspring also resulted in a lower E/A ratio (-0.25, P ¼ 0.002). Neither in parents nor in offspring, left ventricular mass index was associated with the C825T polymorphism. In conclusion, in TT homozygotes of both generations, early left ventricular relaxation was reduced. In TT homozygous parents, the latter observation might be because of the higher systolic pressure associated with the TT genotype.

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“…This promotes the influx of calcium into the cytosol of the cardiomyocyte, causing actin-myosin myofibrillar cross-linking, which results in cellular contraction (Fig. 2) [44].…”

Section: Systolic Dysfunctionmentioning

confidence: 99%

Cirrhotic cardiomyopathy

2008

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Cirrhotic cardiomyopathy is a recently recognized condition in cirrhosis consisting of systolic incompetence under condition of stress, diastolic dysfunction related to altered diastolic relaxation, and electrophysiological abnormalities in the absence of any known cardiac disease. It can be diagnosed by using a combination of electrocardiograph, 2-dimensional echocardiography, and various serum markers such as brain natriuretic factor. The underlying pathogenetic mechanisms include abnormalities in the b-adrenergic signaling pathway, altered cardiomyocyte membrane fluidity, increased myocardial fibrosis, cardiomyocyte hypertrophy, and ion channel defects. Various compounds for which levels are elevated in cirrhosis such as nitric oxide and carbon monoxide can also exert a negative inotropic effect on the myocardium, whereas excess sodium and volume retention can lead to myocardial hypertrophy. Various toxins can also aggravate the ion channel defects, thereby widening the QRS complex causing prolonged QT intervals. Clinically, systolic incompetence is most evident when cirrhotic patients are placed under stress, whether physical or pharmacological, or when the extent of peripheral arterial vasodilatation demands an increased cardiac output as in the case of bacterial infections. Acute volume overload such as immediately after insertion of a transjugular intrahepatic portosystemic shunt or after liver transplantation can also tip these cirrhotic patients into cardiac failure. Treatment of cirrhotic cardiomyopathy is unsatisfactory. There is some evidence that b-blockade may help some cirrhotic patients with baseline prolonged QT interval. Long-term aldosterone antagonism may help reduce myocardial hypertrophy. Future studies should include further elucidation of pathogenetic mechanisms so as to develop effective treatment strategies.

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Recent Advances in Cardiac β ₂ -Adrenergic Signal Transduction

Cited by 223 publications

References 84 publications

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

Cirrhotic cardiomyopathy

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Recent Advances in Cardiac β 2 -Adrenergic Signal Transduction

Cited by 223 publications

References 84 publications

Cardioprotection specific for the G protein G i2 in chronic adrenergic signaling through β 2 -adrenoceptors

Cardioprotection specific for the G protein G i2 in chronic adrenergic signaling through β 2 -adrenoceptors

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein β3-subunit polymorphism C825T in White Europeans

Cirrhotic cardiomyopathy

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Product

Resources

About

Recent Advances in Cardiac β ₂ -Adrenergic Signal Transduction

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors