Myocardial Gi -protein levels in patients with hypertensive cardiac hypertrophy, ischemic heart disease and cardiogenic shock

Böhm, Michael; Kirchmayr, Rita; Erdmann, E

doi:10.1016/s0008-6363(95)00089-5

Cited by 20 publications

(9 citation statements)

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“…For example, transgenic mice that overexpress either G␣ s , G␣ i , or G␣ q show cardiac hypertrophy, with varying levels of interstitial fibrosis, hyperproliferation, hypercellularity, and apoptosis. [41][42][43] Similar studies have been performed by expressing an active mutant of Ras within the heart. 44 These mice manifest cardiac hypertrophy and myofibrillar disarray.…”

Section: Discussionmentioning

confidence: 80%

Caveolin-1/3 Double-Knockout Mice Are Viable, but Lack Both Muscle and Non-Muscle Caveolae, and Develop a Severe Cardiomyopathic Phenotype

Park

Woodman

Schubert

et al. 2002

The American Journal of Pathology

192

147

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The caveolin gene family consists of caveolins 1, 2, and 3. Caveolins 1 and 2 are co-expressed in many cell types, such as endothelial cells, fibroblasts, smooth muscle cells and adipocytes, where they form a heteroligomeric complex. In contrast, the expression of caveolin-3 is muscle-specific. Thus, the expression of caveolin-1 is required for caveolae formation in nonmuscle cells, while the expression of caveolin-3 drives caveolae formation in striated muscle cell types (cardiac and skeletal). To create a truly caveolae-deficient mouse, we interbred Cav-1 null mice and Cav-3 null mice to generate Cav-1/Cav-3 double-knockout (Cav-1/3 dKO) mice. Here, we report that Cav-1/3 dKO mice are viable and fertile, despite the fact that they lack morphologically identifiable caveolae in endothelia, adipocytes, smooth muscle cells, skeletal muscle fibers, and cardiac myocytes. We also show that these mice are deficient in all three caveolin gene products, as caveolin-2 is unstable in the absence of caveolin-1. Interestingly, Cav-1/3 dKO mice develop a severe cardiomyopathy. Caveolae are 50-to 100-nm omega-shaped invaginations of the plasma membrane found in various tissue types. The principal structural proteins of caveolar membranes are encoded by the caveolin gene family (caveolin-1, -2, and -3). Caveolin-1 and -2 are co-expressed in numerous tissue types, with particularly high expression in adipocytes, endothelial cells, fibroblasts, and epithelial cells.1,2 Caveolin-3, on the other hand, is muscle-specific, being highly expressed in all muscle tissues, such as skeletal muscle, diaphragm, and heart. 3,4 Caveolin-1 and -3 form ϳ350-kd homo-oligomers made up of ϳ14 -16 caveolin monomers. These homooligomers serve as the basic structural units that drive the formation of caveolae membranes. In contrast, Cav-2 either homodimerizes or forms high molecular mass hetero-oligomers with Cav-1.5-7 Cav-1 and Cav-3 are both independently necessary and sufficient to drive caveolae formation in heterologous expression systems, while Cav-2 requires the presence of Cav-1 for proper membrane targeting and stabilization. In the absence of

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Section: Discussionmentioning

confidence: 80%

Caveolin-1/3 Double-Knockout Mice Are Viable, but Lack Both Muscle and Non-Muscle Caveolae, and Develop a Severe Cardiomyopathic Phenotype

Park

Woodman

Schubert

et al. 2002

The American Journal of Pathology

192

147

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“…Third, autoantibodies that bind to and cause signaling through the G i -coupled M2 muscarinic receptor are found in up to 40% of patients with IDC (17,18). Despite the clinical association between increased G i signaling and human IDC, many investigators have proposed that this signaling is a compensatory response to the ''hyperadrenergic state'' of heart failure (16,(19)(20)(21). Recent studies in transgenic and knockout mouse models have implicated cell-signaling molecules and myocyte structural proteins in the development (22) and potential treatment (23) of cardiomyopathy.…”

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confidence: 99%

Conditional expression of a G _i -coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy

Redfern

Degtyarev²,

Kwa³

et al. 2000

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

155

122

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Cardiomyopathy is a major cause of morbidity and mortality. Ventricular conduction delay, as shown by prolonged deflections in the electrocardiogram caused by delayed ventricular contraction (wide QRS complex), is a common feature of cardiomyopathy and is associated with a poor prognosis. Although the G i-signaling pathway is up-regulated in certain cardiomyopathies, previous studies suggested this up-regulation was compensatory rather than a potential cause of the disease. Using the tetracycline transactivator system and a modified G i-coupled receptor (Ro1), we provide evidence that increased Gi signaling in mice can result in a lethal cardiomyopathy associated with a wide QRS complex arrhythmia. Induced expression of Ro1 in adult mice resulted in a >90% mortality rate at 16 wk, whereas suppression of Ro1 expression after 8 wk protected mice from further mortality and allowed partial improvement in systolic function. Results of DNA-array analysis of over 6,000 genes from hearts expressing Ro1 are consistent with hyperactive G i signaling. DNA-array analysis also identified known markers of cardiomyopathy and hundreds of previously unknown potential diagnostic markers and therapeutic targets for this syndrome. Our system allows cardiomyopathy to be induced and reversed in adult mice, providing an unprecedented opportunity to dissect the role of G i signaling in causing cardiac pathology.G proteins ͉ signal transduction ͉ gene expression ͉ genome ͉ bioinformatics I diopathic dilated cardiomyopathy (IDC) is a major cause of heart failure characterized by cardiac dilation and reduced systolic function. In the United States, about half of the cases of dilated cardiomyopathy are associated with myocarditis or coronary artery disease, and half are considered idiopathic (1-4). Ventricular conduction delay, as shown by a prolonged depolarization in the electrocardiogram (wide QRS complex), is associated with up to 70% of IDC cases (5) and is an independent risk factor for death among IDC patients (6, 7). Several lines of evidence implicate altered G i signaling in the development of cardiomyopathies such as IDC, but a direct relationship between G i signaling and cardiomyopathy has not been demonstrated in vivo. We recently created a system that utilizes a specifically designed G i -coupled receptor and inducible gene expression techniques to control G i signaling in the adult mouse heart (8).With over 2

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“…Of particular relevance to the present study is the finding that G i␣ levels were elevated by 225% in patients who died of "catecholamine refractory" cardiogenic shock after myocardial infarction. 3 It may therefore be that a similar pathophysiological mechanism is responsible for both cardiogenic shock and brain-death-induced acute heart failure and that the 2 conditions are, in clinical terms, the same entity.…”

Section: Discussionmentioning

confidence: 99%

“…2 Furthermore, end-stage failing myocardium is desensitized to ␤-agonists because of ␤-adrenoceptor (␤-AR) downregulation coupled with upregulation of the inhibitory G protein G i␣ . 3,4 We have characterized the contractile behavior of cells and trabeculae from unused donor hearts and compared it with that seen in hearts with end-stage failure. Myocardial samples were analyzed for abundance of the key calcium-handling proteins SERCA2, sodium calcium exchanger (NCX), and phospholamban (PLB).…”

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confidence: 99%

Myocardial Dysfunction in Donor Hearts

et al. 1999

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Background-Potential cardiac donors show various degrees of myocardial dysfunction, and the most severely affected hearts are unsuitable for transplantation. The cause of this acute heart failure is poorly understood. We investigated whether alterations in calcium-handling proteins, ␤-adrenoceptor density, or the inhibitory G protein G i␣ could account for this phenomenon in unused donor hearts (nϭ4 to 8). We compared these with end-stage failing hearts (nϭ14 to 16) and nonfailing hearts (nϭ3 to 12). Methods and Results-Myocardial samples were obtained from unused donor hearts displaying ejection fractions Ͻ30%. Both trabeculae and isolated myocytes responded as poorly as those from the group of failing hearts to increasing stimulation frequency with regard to inotropic function in vitro. Immunodetectable abundance of sarcoplasmic reticulum calcium-ATPase and sodium calcium exchanger were greater (177%; PϽ0.01) and smaller (29%; PϽ0.01), respectively, in the unused donor hearts relative to the failing group, which suggests that alterations of these proteins are not a common cause of contractile dysfunction in the 2 groups. Myocytes from the unused donor group were desensitized to isoprenaline to a similar degree as those from the failing heart group. However, ␤-adrenoceptor density was reduced in the failing (PϽ0.001) but not in the unused donor heart group (Pϭ0.37) relative to the nonfailing heart group (nϭ5). G i␣ activity was increased in samples from unused donor and failing hearts relative to nonfailing hearts (PϽ0.05). Conclusions-Increased activity of the inhibitory G protein G i␣ is a significant contributory factor for impaired contractility in these acutely failing donor hearts. (Circulation. 1999;99:2565-2570.)

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Myocardial Gi -protein levels in patients with hypertensive cardiac hypertrophy, ischemic heart disease and cardiogenic shock

Cited by 20 publications

References 0 publications

Caveolin-1/3 Double-Knockout Mice Are Viable, but Lack Both Muscle and Non-Muscle Caveolae, and Develop a Severe Cardiomyopathic Phenotype

Caveolin-1/3 Double-Knockout Mice Are Viable, but Lack Both Muscle and Non-Muscle Caveolae, and Develop a Severe Cardiomyopathic Phenotype

Conditional expression of a G _i -coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy

Myocardial Dysfunction in Donor Hearts

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Myocardial Gi -protein levels in patients with hypertensive cardiac hypertrophy, ischemic heart disease and cardiogenic shock

Cited by 20 publications

References 0 publications

Caveolin-1/3 Double-Knockout Mice Are Viable, but Lack Both Muscle and Non-Muscle Caveolae, and Develop a Severe Cardiomyopathic Phenotype

Caveolin-1/3 Double-Knockout Mice Are Viable, but Lack Both Muscle and Non-Muscle Caveolae, and Develop a Severe Cardiomyopathic Phenotype

Conditional expression of a G i -coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy

Myocardial Dysfunction in Donor Hearts

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Conditional expression of a G _i -coupled receptor causes ventricular conduction delay and a lethal cardiomyopathy