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Intracellular β-blockade: overexpression of Gαi2 depresses the β-adrenergic response in intact myocardium
- Source :
- Cardiovascular Research. 55:300-308
- Publication Year :
- 2002
- Publisher :
- Oxford University Press (OUP), 2002.
-
Abstract
- Increased levels of inhibitory G proteins have been observed in heart failure, but their physiological relevance in mediating the reduced beta-adrenergic response is largely unknown.To evaluate the functional consequences of Galpha(i2) overexpression, we studied myocardial contraction in intact isometric contracting cardiac rabbit trabeculae and isolated myocytes after adenovirus-mediated gene transfer of Galpha(i2).Neither Galpha(i2) nor lacZ (control) overexpression altered baseline contractile force. After 72 h of continuous contractions, developed force (F(dev)) increased after addition of 1 microM isoproterenol by 28.5+/-9.7 mN/mm(2) in the control group, which was unchanged from the initial response at t=0 h (23.7+/-3.8 mN/mm(2)). In sharp contrast, in preparations transfected with AdGalpha(i2), the response to isoproterenol was significantly attenuated (5.9+/-2.0 vs. 27.6+/-4.2 mN/mm(2), t=72 vs. 0 h, respectively, P0.01). In a primary culture of transfected isolated myocytes from a nearly identical baseline, isoproterenol increased cell shortening by 3.1+/-0.6% in the lacZ transfected myocytes, but only by 1.3+/-0.5% in Galpha(i2) transfected myocytes (t=72 h, P0.01). In Galpha(i2) transfected myocytes, pertussis toxin restored beta-adrenergic responsiveness, indicating specificity of attenuation by the transgene.Overexpression of Galpha(i2) attenuates the positive inotropic effects of beta-adrenergic stimulation in myocardium. In addition, the method we developed allows investigation of a causal link between altered protein expression and subsequent alterations in contractile function in a physiological relevant in vitro manner.
- Subjects :
- medicine.medical_specialty
Cardiotonic Agents
Contraction (grammar)
Physiology
G protein
Genetic Vectors
Cell Culture Techniques
Stimulation
GTP-Binding Protein alpha Subunits, Gi-Go
030204 cardiovascular system & hematology
Biology
Transfection
Pertussis toxin
Adenoviridae
Contractility
03 medical and health sciences
0302 clinical medicine
Proto-Oncogene Proteins
Physiology (medical)
Isoprenaline
Internal medicine
medicine
Animals
Myocyte
Transgenes
Virulence Factors, Bordetella
Cell Size
030304 developmental biology
0303 health sciences
Myocardium
Isoproterenol
Adrenergic beta-Agonists
Myocardial Contraction
Up-Regulation
3. Good health
Endocrinology
Pertussis Toxin
Rabbits
GTP-Binding Protein alpha Subunit, Gi2
Cardiology and Cardiovascular Medicine
Intracellular
medicine.drug
Subjects
Details
- ISSN :
- 00086363
- Volume :
- 55
- Database :
- OpenAIRE
- Journal :
- Cardiovascular Research
- Accession number :
- edsair.doi.dedup.....330dafe510f2e0ab250ae649413aab73