Dataset Information

Transgenic Galphaq overexpression induces cardiac contractile failure in mice.

ABSTRACT: The critical cell signals that trigger cardiac hypertrophy and regulate the transition to heart failure are not known. To determine the role of Galphaq-mediated signaling pathways in these events, transgenic mice were constructed that overexpressed wild-type Galphaq in the heart using the alpha-myosin heavy chain promoter. Two-fold overexpression of Galphaq showed no detectable effects, whereas 4-fold overexpression resulted in increased heart weight and myocyte size along with marked increases in atrial naturietic factor ( approximately 55-fold), beta-myosin heavy chain ( approximately 8-fold), and alpha-skeletal actin ( approximately 8-fold) expression, and decreased ( approximately 3-fold) beta-adrenergic receptor-stimulated adenylyl cyclase activity. All of these signals have been considered markers of hypertrophy or failure in other experimental systems or human heart failure. Echocardiography and in vivo cardiac hemodynamic studies indeed revealed impaired intrinsic contractility manifested as decreased fractional shortening (19 +/- 2% vs. 41 +/- 3%), dP/dt max, a negative force-frequency response, an altered Starling relationship, and blunted contractile responses to the beta-adrenergic agonist dobutamine. At higher levels of Galphaq overexpression, frank cardiac decompensation occurred in 3 of 6 animals with development of biventricular failure, pulmonary congestion, and death. The element within the pathway that appeared to be critical for these events was activation of protein kinase Cepsilon. Interestingly, mitogen-activated protein kinase, which is postulated by some to be important in the hypertrophy program, was not activated. The Galphaq overexpressor exhibits a biochemical and physiologic phenotype resembling both the compensated and decompensated phases of human cardiac hypertrophy and suggests a common mechanism for their pathogenesis.

SUBMITTER: D'Angelo DD

PROVIDER: S-EPMC21567 | biostudies-literature | 1997 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Transgenic Galphaq overexpression induces cardiac contractile failure in mice.

D'Angelo D D DD Sakata Y Y Lorenz J N JN Boivin G P GP Walsh R A RA Liggett S B SB Dorn G W GW

Proceedings of the National Academy of Sciences of the United States of America 19970701 15

The critical cell signals that trigger cardiac hypertrophy and regulate the transition to heart failure are not known. To determine the role of Galphaq-mediated signaling pathways in these events, transgenic mice were constructed that overexpressed wild-type Galphaq in the heart using the alpha-myosin heavy chain promoter. Two-fold overexpression of Galphaq showed no detectable effects, whereas 4-fold overexpression resulted in increased heart weight and myocyte size along with marked increases ...[more]

PMID: 9223325

Similar Datasets

Project description:BACKGROUND:LARGE is one of seven putative or demonstrated glycosyltransferase enzymes defective in a common group of muscular dystrophies with reduced glycosylation of ?-dystroglycan. Overexpression of LARGE induces hyperglycosylation of ?-dystroglycan in both wild type and in cells from dystroglycanopathy patients, irrespective of their primary gene defect, restoring functional glycosylation. Viral delivery of LARGE to skeletal muscle in animal models of dystroglycanopathy has identical effects in vivo, suggesting that the restoration of functional glycosylation could have therapeutic applications in these disorders. Pharmacological strategies to upregulate Large expression are also being explored. METHODOLOGY/PRINCIPAL FINDINGS:In order to asses the safety and efficacy of long term LARGE over-expression in vivo, we have generated four mouse lines expressing a human LARGE transgene. On observation, LARGE transgenic mice were indistinguishable from the wild type littermates. Tissue analysis from young mice of all four lines showed a variable pattern of transgene expression: highest in skeletal and cardiac muscles, and lower in brain, kidney and liver. Transgene expression in striated muscles correlated with ?-dystroglycan hyperglycosylation, as determined by immunoreactivity to antibody IIH6 and increased laminin binding on an overlay assay. Other components of the dystroglycan complex and extracellular matrix ligands were normally expressed, and general muscle histology was indistinguishable from wild type controls. Further detailed muscle physiological analysis demonstrated a loss of force in response to eccentric exercise in the older, but not in the younger mice, suggesting this deficit developed over time. However this remained a subclinical feature as no pathology was observed in older mice in any muscles including the diaphragm, which is sensitive to mechanical load-induced damage. CONCLUSIONS/SIGNIFICANCE:This work shows that potential therapies in the dystroglycanopathies based on LARGE upregulation and ?-dystroglycan hyperglycosylation in muscle should be safe.

Project description:BackgroundTransgenic mice with transient cardiac expression of constitutively active Galpha q (Gαq-TG) exhibt progressive heart failure and ventricular arrhythmias after the initiating stimulus of transfected constitutively active Gαq becomes undetectable. However, the mechanisms are still unknown. We examined the effects of chronic administration of olmesartan on heart failure and ventricular arrhythmia in Gαq-TG mice.Methodology/principal findingsOlmesartan (1 mg/kg/day) or vehicle was chronically administered to Gαq-TG from 6 to 32 weeks of age, and all experiments were performed in mice at the age of 32 weeks. Chronic olmesartan administration prevented the severe reduction of left ventricular fractional shortening, and inhibited ventricular interstitial fibrosis and ventricular myocyte hypertrophy in Gαq-TG. Electrocardiogram demonstrated that premature ventricular contraction (PVC) was frequently (more than 20 beats/min) observed in 9 of 10 vehicle-treated Gαq-TG but in none of 10 olmesartan-treated Gαq-TG. The collected QT interval and monophasic action potential duration in the left ventricle were significantly shorter in olmesartan-treated Gαq-TG than in vehicle-treated Gαq-TG. CTGF, collagen type 1, ANP, BNP, and β-MHC gene expression was increased and olmesartan significantly decreased the expression of these genes in Gαq-TG mouse ventricles. The expression of canonical transient receptor potential (TRPC) 3 and 6 channel and angiotensin converting enzyme (ACE) proteins but not angiotensin II type 1 (AT1) receptor was increased in Gαq-TG ventricles compared with NTG mouse ventricles. Olmesartan significantly decreased TRPC6 and tended to decrease ACE expressions in Gαq-TG. Moreover, it increased AT1 receptor in Gαq-TG.Conclusions/significanceThese findings suggest that angiotensin II type 1 receptor activation plays an important role in the development of heart failure and ventricular arrhythmia in Gαq-TG mouse model of heart failure.

Dataset Information

Transgenic Galphaq overexpression induces cardiac contractile failure in mice.

Publications

Transgenic Galphaq overexpression induces cardiac contractile failure in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets