Increase in functional activity rather than in amount of Gi-  in failing human heart with dilated cardiomyopathy

Fu, Lei; Liang, Qi-Ming; Waagstein, Finn; Hoebeke, Johan; Sylvén, Christer; Jansson, Emmelie Å.; Sótonyi, Péter; Hjalmarson, Åke

doi:10.1093/cvr/26.10.950

Cited by 33 publications

(11 citation statements)

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“…Recent studies in mice and humans suggest that increases or dysregulation of G i signaling may underlie some human dilated cardiomyopathies 9,21,22 . Our control of Ro1 expression and activation will allow us to test both the short-and longterm biochemical, pathological, and gene expression effects induced by G i signaling in the heart.…”

Section: Discussionmentioning

confidence: 99%

Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice

et al. 1999

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To control G protein signaling in vivo, we have modified G protein-coupled receptors to respond exclusively to synthetic small molecule agonists and not to their natural agonist(s). These engineered receptors are designated RASSLs (receptor activated solely by a synthetic ligand). A prototype RASSL (Ro1) based on the Gi-coupled K opioid receptor was expressed in transgenic mice under the control of the tetracycline transactivator (tet) system. Activation of Ro1 expressed in the heart decreased heart rate by up to 80%, an expected effect of increased Gi signaling. Maximal heart rate changes occurred in less than 1 min, demonstrating the speed of this inducible signaling system. This Ro1-mediated slowing of heart rate was also subject to desensitization, which lasted more than 24 h. Both the initial effect on heart rate and the desensitization occurred, even though Ro1 is derived from a human opioid receptor not normally involved in heart rate control. In addition, the tet system was used to induce Ro1 expression in hepatocytes and salivary gland, where Gi signaling is known to control physiologic events such as proliferation and secretion. These studies demonstrate that a RASSL can be inducibly expressed in several mouse tissues and used in vivo to activate G protein signaling in a controllable fashion.

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Section: Discussionmentioning

confidence: 99%

Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice

et al. 1999

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“…Feldman et al (1988) observed the increased activity of α G40 complex in the human failing heart and considered as a possible new marker for the severity of failing heart. Fu et al (1992) also concluded that the role of G i protein is crucial in the failing heart but it was observed an increase in functional activity rather than in its amount. In 1997 Ping et al (1997) during the pacing induced congestive heart failure (CHF) examined the alteration of β-ARs, AC activity and GRKs.…”

Section: Clinical Implications Of Alterations In β-Adrenoceptor Mechamentioning

confidence: 99%

β-adrenergic receptor responsiveness in aging heart and clinical implications

et al. 2014

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Elderly healthy individuals have a reduced exercise tolerance and a decreased left ventricle inotropic reserve related to increased vascular afterload, arterial-ventricular load mismatching, physical deconditioning and impaired autonomic regulation (the so called “β-adrenergic desensitization”). Adrenergic responsiveness is altered with aging and the age-related changes are limited to the β-adrenergic receptor density reduction and to the β-adrenoceptor-G-protein(s)-adenylyl cyclase system abnormalities, while the type and level of abnormalities change with species and tissues. Epidemiological studies have shown an high incidence and prevalence of heart failure in the elderly and a great body of evidence correlate the changes of β-adrenergic system with heart failure pathogenesis. In particular it is well known that: (a) levels of cathecolamines are directly correlated with mortality and functional status in heart failure, (b) β1-adrenergic receptor subtype is down-regulated in heart failure, (c) heart failure-dependent cardiac adrenergic responsiveness reduction is related to changes in G proteins activity. In this review we focus on the cardiovascular β-adrenergic changes involvement in the aging process and on similarities and differences between aging heart and heart failure.

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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.…”

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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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Increase in functional activity rather than in amount of Gi- in failing human heart with dilated cardiomyopathy

Abstract: These results suggest that in the failing human heart, there is an increase in functional activity rather than in amount of Gi, and an important part of functional expression of Gi-alpha may be regulated at the post-translational level.

Cited by 33 publications

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Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice

Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice

β-adrenergic receptor responsiveness in aging heart and clinical implications

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

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Increase in functional activity rather than in amount of Gi- in failing human heart with dilated cardiomyopathy

Abstract: These results suggest that in the failing human heart, there is an increase in functional activity rather than in amount of Gi, and an important part of functional expression of Gi-alpha may be regulated at the post-translational level.

Cited by 33 publications

References 0 publications

Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice

Conditional expression and signaling of a specifically designed Gi-coupled receptor in transgenic mice

β-adrenergic receptor responsiveness in aging heart and clinical implications

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