Cardiac Effects of Attenuating Gsα - Dependent Signaling

Streit, Marcus R.; Weiss, Claus; Meyer, Sören; Ochs, Marco; Hagenmueller, Marco; Riffel, Johannes; Buss, Sebastian J.; Heger, Thomas; Katus, Hugo A.; Hardt, Stefan E.

doi:10.1371/journal.pone.0146988

Cited by 4 publications

(4 citation statements)

References 32 publications

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“…Second, the different methods may be responsible. For example, in a previous study [ 29 ], Gsα expression was found to be attenuated through the systemic overexpression of its dominant-negative mutant; however, the Gsα deletion in our study was performed using tamoxifen-inducible Cre recombinase, which might have high and long-term efficiency. Future studies should provide in-depth information on the influence of genetic Gsα deletion over an extended period in Gsα CMKO mice.…”

Section: Discussionmentioning

confidence: 89%

“…Young transgenic mice with cardiac-specific Gsα overexpression only exhibited an enhanced response to catecholamines but developed dilated cardiomyopathy as they aged [ 25 – 28 ]. Another study reported that the attenuation of Gsα expression led to bradycardia and protected against isoproterenol-induced hypertrophy [ 29 ]. However, in our study, Gsα CMKO mice showed cardiac dysfunction and cardiac remodeling at a young age, and there were no significant differences in heart rate under anesthetic conditions between Gsα CMKO and control mice.…”

Section: Discussionmentioning

confidence: 99%

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Gsα deficiency facilitates cardiac remodeling via CREB/ Bmp10-mediated signaling

Yin

Zhao

et al. 2021

Cell Death Discov.

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The stimulatory G-protein alpha subunit (Gsα), a ubiquitously expressed protein, mediates G-protein receptor-stimulated signal transduction. To investigate the functions of Gsα in cardiomyocytes. We developed transverse aortic constriction (TAC)-induced heart failure mouse models and tamoxifen-inducible transgenic mice with cardiac-specific Gsα disruption. We detected alterations in Gsα expression in TAC-induced heart failure mice. Moreover, we examined cardiac function and structure in mice with genetic Gsα deletion and investigated the underlying molecular mechanisms of Gsα function. We found that Gsα expression increased during the compensated cardiac hypertrophy period and decreased during the heart failure period. Moreover, cardiac-specific Gsα disruption deteriorated cardiac function and induced severe cardiac remodeling. Mechanistically, Gsα disruption decreased CREB1 expression and inhibited the Bmp10-mediated signaling pathway. In addition, we found that Gsα regulates Bmp10 expression through the binding of CREB1 to the Bmp10 promoter. Our results suggest that fluctuations in Gsα levels may play a vital role in the development of heart failure and that loss of Gsα function facilitates cardiac remodeling.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Gsα deficiency facilitates cardiac remodeling via CREB/ Bmp10-mediated signaling

Yin

Zhao

et al. 2021

Cell Death Discov.

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“…The endothelium-specific Gsα knockout mice were embryonic lethal due to abnormal vessel structure and serious bleeding [ 18 ]. However, mice overexpressing a dominant negative Gsα-mutant in heart leads to decreased β-adrenergic responsiveness and is protective against ISO-induced hypertrophy [ 19 ]. In our recent report, we found that Gsα could regulate intestinal smooth muscle contraction in mice [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Smooth muscle-specific Gsα deletion exaggerates angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo

Qin

Tian

et al. 2019

Journal of Molecular and Cellular Cardiology

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Objective: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without an effective pharmaceutical treatment. Genetic studies have proved the involvement of smooth muscle phenotype switch in the development of AAA. The alpha subunit of the heterotrimeric G stimulatory protein (Gsα) mediates receptorstimulated production of cyclic adenosine monophosphate (cAMP). However, the role of smooth muscle Gsα in AAA formation remains unknown. Approach and results: In this study, mice with knockout of smooth muscle-specific Gsα (Gsα SMKO ) were generated by cross-breeding Gsα flox/flox mice with SM22-CreER T2 transgenic mice, induced in adult mice by tamoxifen treatment. Gsα deficiency induced a smooth muscle phenotype switch from a contractile to a synthetic state. Mechanically, Gsα deletion reduced cAMP level and increased the level of human antigen R (HuR), which binds with the adenylate uridylate-rich elements of the 3′ untranslated region of Krüppel-like factor 4 (KLF4) mRNA, thereby increasing the stability of KLF4. Moreover, genetic knockdown of HuR or KLF4 rescued the phenotype switch in Gsα-deficient smooth muscle cells. Furthermore, with acute infusion of angiotensin II, the incidence of AAA was markedly higher in ApoE −/− /Gsα SMKO than ApoE −/− /Gsα flox/flox mice and induced increased elastic lamina degradation and aortic expansion. Finally, the levels of Gsα and SM α-actin were significantly lower while those of HuR and KLF4 were higher in human AAA samples than adjacent nonaneurysmal aortic sections. Conclusions: Gsα may play a protective role in AAA formation by regulating the smooth muscle phenotype switch and could be a potential therapeutic target for AAA disease.is often accompanied by downregulation of multiple contractile proteins in aortic smooth muscle cells (SMCs) [4,5]. Furthermore, aortic intimal layer injury and inflammatory cell infiltration participate in the aneurysm progression via complicated mechanisms such as cytokine secretion and increased reactive oxygen species levels [3,6]. Finally, vascular collagen and elastin extracellular matrix is thought to undergo degradation by matrix metalloproteinases and contribute to AAA

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“…Overexpression of cyclic AMP-hydrolyzing protein phosphodiesterase 4B (PDE4B), a key negative regulator of cardiac

1 -AR stimulation, was shown to blunt the

1 -AR signaling whereas its deficiency resulted in abnormal

-handling in pressure overload induced cardiac hypertrophy [ 185 ]. Furthermore, overexpression of a dominant negative mutant of Gs

-proteins decreased

1 -AR responsiveness and protected against isoproterenol-induced cardiac hypertrophy in transgenic Gs

-DN-mice [ 186 ]. These observations showing variable changes in

1 -AR signaling transduction system due to pressure overload also support the view that alterations in

1 -AR signaling are dependent upon the stage of cardiac hypertrophy and heart failure.…”

Section: Dependence Of Changes In 1 -Ar Signal...mentioning

confidence: 99%

Status of β1-Adrenoceptor Signal Transduction System in Cardiac Hypertrophy and Heart Failure

Dhalla,

Bhullar,

Adameova

et al. 2023

Rev. Cardiovasc. Med.

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Although 1 -adrenoceptor ( 1 -AR) signal transduction, which maintains cardiac function, is downregulated in failing hearts, the mechanisms for such a defect in heart failure are not fully understood. Since cardiac hypertrophy is invariably associated with heart failure, it is possible that the loss of 1 -AR mechanisms in failing heart occurs due to hypertrophic process. In this regard, we have reviewed the information from a rat model of adaptive cardiac hypertrophy and maladaptive hypertrophy at 4 and 24 weeks after inducing pressure overload as well as adaptive cardiac hypertrophy and heart failure at 4 and 24 weeks after inducing volume overload, respectively. Varying degrees of alterations in 1 -AR density as well as isoproterenol-induced increases in cardiac function, intracellular -concentration in cardiomyocytes and adenylyl cyclase activity in crude membranes have been reported under these hypertrophic conditions. Adaptive hypertrophy at 4 weeks of pressure or volume overload showed unaltered or augmented increases in the activities of different components of 1 -AR signaling. On the other hand, maladaptive hypertrophy due to pressure overload and heart failure due to volume overload at 24 weeks revealed depressions in the activities of 1 -AR signal transduction pathway. These observations provide evidence that 1 -AR signal system is either unaltered or upregulated in adaptive cardiac hypertrophy and downregulated in maladaptive cardiac hypertrophy or heart failure. Furthermore, the information presented in this article supports the concept that downregulation of 1 -AR mechanisms in heart failure or maladaptive cardiac hypertrophy is not due to hypertrophic process per se . It is suggested that a complex mechanism involving the autonomic imbalance may be of a critical importance in determining differential alterations in non-failing and failing hearts.

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Cardiac Effects of Attenuating Gsα - Dependent Signaling

Cited by 4 publications

References 32 publications

Gsα deficiency facilitates cardiac remodeling via CREB/ Bmp10-mediated signaling

Gsα deficiency facilitates cardiac remodeling via CREB/ Bmp10-mediated signaling

Smooth muscle-specific Gsα deletion exaggerates angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo

Status of β1-Adrenoceptor Signal Transduction System in Cardiac Hypertrophy and Heart Failure

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