Immunodetectable levels of the inhibitory guanine nucleotide-binding regulatory proteins in failing human heart: Discordance with measurements of adenylate cyclase activity and levels of pertussis toxin substrate

Feldman, Arthur M.; Jackson, Donald; Bristow, Michael R.; Cates, A. E.; Dop, Cornelis Van

doi:10.1016/0022-2828(91)90168-l

Cited by 52 publications

(11 citation statements)

References 37 publications

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“…However, in our study, the amount detected by CT ribosylation is different from that detected by using specific G s ␣ antibody. Similar situations have been observed regarding G i ␣ protein content with PT and specific antibody for G i ␣ protein by other investigators (13). This may be due to the intrinsic character of these two techniques.…”

Section: Discussionsupporting

confidence: 87%

Alterations of adenylyl cyclase and G proteins in aortocaval shunt-induced heart failure

Wang¹,

Sentex²,

Chapman³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Unlike most other experimental models of congestive heart failure, the volume overload model induced by aortocaval shunt (AVS) in rats was found to exhibit enhanced beta-adrenoceptor (beta-AR) signaling. To study whether the adenylyl cyclase (AC)-G protein system is involved in such a change, we examined cardiac AC activity and protein content as well as G(s)alpha and G(i)alpha activities, protein contents, and mRNA levels in both left (LV) and right (RV) ventricles at the failing stage (16 wk after surgery). Basal and forskolin-stimulated AC activities were significantly increased in both LV and RV from the failing hearts; this change was associated with an upregulation of type V/VI AC protein. In contrast to 5'-guanylyl imidodiphosphate and NaF, the stimulatory effect of isoproterenol on AC was increased in the failing heart. Although G(s)alpha and G(i)alpha protein contents in the failing hearts were not altered, the mRNA level for G(s)alpha was decreased by 20% and that for G(i)alpha was increased by 20%. In addition, the activity of G(s)alpha, but not G(i)alpha, as assessed by toxin-catalyzed ADP ribosylation, was significantly decreased in the failing heart. Losartan and imidapril treatments improved cardiac function and attenuated alterations in mRNA levels for G(s)alpha and G(i)alpha proteins, as well as G(s)alpha activity, without affecting changes in AC protein content or activities in heart failure due to volume overload. These data suggest that increased AC activity may contribute to the enhanced beta-AR signaling in the AVS model of heart failure, whereas alterations in gene expression for G proteins may be of an adaptive nature at this stage of heart failure.

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Section: Discussionsupporting

confidence: 87%

Alterations of adenylyl cyclase and G proteins in aortocaval shunt-induced heart failure

Wang¹,

Sentex²,

Chapman³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…The G ␣s proteins may also be in the cytosolic fraction where they are unavailable for signaling (15). The functional activity of G ␣i in heart failure is also increased (8), which would make the inhibitory effect higher despite the lack of an increase in actual protein levels. Our cAMP measurements further argue that the sole increase of ␤ 1 AR and G ␣s is not enough to enhance cAMP production, since ␤AR stimulation in our study did not produce higher levels of cAMP in the hearts expressing more G ␣s .…”

Section: Prenatally Hypoxic Animals Display Signs Of Cardiac Hypertromentioning

confidence: 99%

Prenatal hypoxia programs changes in β-adrenergic signaling and postnatal cardiac contractile dysfunction

Lindgren

Altimiras

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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We have previously demonstrated a programming effect of prenatal hypoxia on the cardiac ␤-adrenergic (␤AR) response. The aim of this study was to determine 1) whether the decrease in ␤AR sensitivity in prenatally hypoxic 5-wk old chicken hearts is linked to changes in ␤ 1AR/␤2ARs, G␣i expression and cAMP accumulation and 2) whether prenatal hypoxia has an effect on heart function in vivo. We incubated eggs in normoxia (N, 21% O 2) or hypoxia from day 0 (H, 14% O 2) and raised the posthatchlings to 5 wk of age. Cardiac ␤ 1AR/␤2ARs were assessed through competitive binding of [ 3 H]CGP-12177 with specific ␤1AR or ␤2AR blockers. G␣s and G␣i proteins were assessed by Western blot and cAMP accumulation by ELISA. Echocardiograms were recorded in anesthetized birds to evaluate diastolic/systolic diameter and heart rate and tissue sections were stained for collagen. We found an increase in relative heart mass, ␤ 1ARs, and G␣s in prenatally hypoxic hearts. cAMP levels after isoproterenol stimulation and collagen content was not changed in H compared with N, but in vivo echocardiograms showed systolic contractile dysfunction. The changes in ␤AR and G protein subtypes may be indicative of an early compensatory stage in the progression of cardiac dysfunction, further supported by the cardiac hypertrophy and systolic contractile dysfunction. We suggest that it is not the changes in the proximal part of the ␤AR system that causes the decreased cardiac contractility, but Ca 2ϩ handling mechanisms further downstream in the ␤AR signaling cascade.␤-adrenergic receptors; G proteins; developmental programming; systolic dysfunction; heart failure THE CONNECTION between low birth weight and increased risk for adult disease is well recognized, and many studies have confirmed the phenomenon of developmental (or fetal) programming of adult cardiovascular disease (1-3, 36). Cardiovascular disease is closely related to changes in ␤-adrenoceptor (␤AR) signaling in the heart (26), but not much is known about how the ␤AR system is affected by prenatal stress such as hypoxia. We previously showed that the response to vascular ␤AR is enhanced in embryos incubated in chronic prenatal hypoxia and that chronic prenatal hypoxia decreases ␤AR sensitivity to epinephrine stimulation in the 5-wk postnatal chicken heart, without changes in receptor density (18). This in vitro evidence indicates that prenatal hypoxia has a programming effect on ␤AR signaling in the adult, but the molecular background of the decreased ␤AR sensitivity in the heart and the in vivo implications of this loss of function are not known.Classic ␤AR signaling starts with a conformational change of the receptor in response to catecholamine stimulation. This enables intracellular association of stimulatory G proteins to the receptor that upon the interaction dissociates into an ␣-subunit (G ␣s ) and a ␤␥ complex. The G ␣s subunit in turn stimulates adenylyl cyclase (AC) to convert ATP to cAMP and cAMP act on kinases responsible for both altering calcium flux in the cell (leading t...

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“…Levels of G␣ i were increased in ventricles of patients with idiopathic DCM (4,8,27). Furthermore, decreased adenylyl cyclase activity (an effect of G i signaling) was found in hearts of patients with DCM (8,9,11). Despite the association between increased G i signaling and DCM, the mechanisms involved remain unclear.…”

mentioning

confidence: 99%

Expression of a G_i-coupled receptor in the heart causes impaired Ca²⁺handling, myofilament injury, and dilated cardiomyopathy

McCloskey

Turcato²,

Wang³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Increased signaling by G(i)-coupled receptors has been implicated in dilated cardiomyopathy. To investigate the mechanisms, we used transgenic mice that develop dilated cardiomyopathy after conditional expression of a cardiac-targeted G(i)-coupled receptor (Ro1). Activation of G(i) signaling by the Ro1 agonist spiradoline caused decreased cellular cAMP levels and bradycardia in Langendorff-perfused hearts. However, acute termination of Ro1 signaling with the antagonist nor-binaltorphimine did not reverse the Ro1-induced contractile dysfunction, indicating that Ro1 cardiomyopathy was not due to acute effects of receptor signaling. Early after initiation of Ro1 expression, there was a 40% reduction in the abundance of the sarcoplasmic reticulum Ca(2+)-ATPase (P < 0.05); thereafter, there was progressive impairment of both Ca(2+) handling and force development assessed with ventricular trabeculae. Six weeks after initiation of Ro1 expression, systolic Ca(2+) concentration was reduced to 0.61 +/- 0.08 vs. 0.91 +/- 0.07 microM for control (n = 6-8; P < 0.05), diastolic Ca(2+) concentration was elevated to 0.41 +/- 0.07 vs. 0.23 +/- 0.06 microM for control (n = 6-8; P < 0.01), and the decline phase of the Ca(2+) transient (time from peak to 50% decline) was slowed to 0.25 +/- 0.02 s vs. 0.13 +/- 0.02 s for control (n = 6-8; P < 0.01). Early after initiation of Ro1 expression, there was a ninefold elevation of matrix metalloproteinase-2 (P < 0.01), which is known to cause myofilament injury. Consistent with this, 6 wk after initiation of Ro1 expression, Ca(2+)-saturated myofilament force in skinned trabeculae was reduced to 21 +/- 2 vs. 38 +/- 0.1 mN/mm(2) for controls (n = 3; P < 0.01). Furthermore, electron micrographs revealed extensive myofilament damage. These findings may have implications for some forms of human heart failure in which increased activity of G(i)-coupled receptors leads to impaired Ca(2+) handling and myofilament injury, contributing to impaired ventricular pump function and heart failure.

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Immunodetectable levels of the inhibitory guanine nucleotide-binding regulatory proteins in failing human heart: Discordance with measurements of adenylate cyclase activity and levels of pertussis toxin substrate

Cited by 52 publications

References 37 publications

Alterations of adenylyl cyclase and G proteins in aortocaval shunt-induced heart failure

Alterations of adenylyl cyclase and G proteins in aortocaval shunt-induced heart failure

Prenatal hypoxia programs changes in β-adrenergic signaling and postnatal cardiac contractile dysfunction

Expression of a G_i-coupled receptor in the heart causes impaired Ca²⁺handling, myofilament injury, and dilated cardiomyopathy

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Immunodetectable levels of the inhibitory guanine nucleotide-binding regulatory proteins in failing human heart: Discordance with measurements of adenylate cyclase activity and levels of pertussis toxin substrate

Cited by 52 publications

References 37 publications

Alterations of adenylyl cyclase and G proteins in aortocaval shunt-induced heart failure

Alterations of adenylyl cyclase and G proteins in aortocaval shunt-induced heart failure

Prenatal hypoxia programs changes in β-adrenergic signaling and postnatal cardiac contractile dysfunction

Expression of a Gi-coupled receptor in the heart causes impaired Ca2+handling, myofilament injury, and dilated cardiomyopathy

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Expression of a G_i-coupled receptor in the heart causes impaired Ca²⁺handling, myofilament injury, and dilated cardiomyopathy