title: Controlled and cardiac-restricted overexpression of the arginine vasopressin V1A receptor causes reversible left ventricular dysfunction through Gαq-mediated cell signaling.
abstract: BACKGROUND
  [Arg8]-vasopressin (AVP) activates 3 G-protein-coupled receptors: V1A, V2, and V1B. The AVP-V1A receptor is the primary AVP receptor in the heart; however, its role in cardiac homeostasis is controversial. To better understand AVP-mediated signaling in the heart, we created a transgenic mouse with controlled overexpression of the V1A receptor.
  
  
  RESULTS
  The V1A receptor transgene was placed under the control of the tetracycline-regulated, cardiac-specific α-myosin heavy chain promoter (V1A-TG). V1A-TG mice had a normal cardiac function phenotype at 10 weeks of age; however, by 24 weeks of age, tetracycline-transactivating factor/V1A-TG mouse hearts had reduced cardiac function, cardiac hypertrophy, and dilatation of the ventricular cavity. Contractile dysfunction was also observed in isolated adult cardiac myocytes. When V1A receptor transgene was induced to be expressed in adult mice (V1A-TG(Ind)), left ventricular dysfunction and dilatation were also seen, albeit at a later time point. Because the V1A receptor mediates cell signaling through Gα(q) protein, we blocked Gα(q) signaling by crossing tetracycline-transactivating factor/V1A mice with transgenic mice that expressed a small inhibitory peptide against Gα(q). Gα(q) blockade abrogated the development of the heart failure phenotype in tetracycline-transactivating factor/V1A-TG mice. The heart failure phenotype could be reversed by administration of doxycycline.
  
  
  CONCLUSIONS
  Our results demonstrate a role for V1A-mediated signaling in the development of heart failure and support a role for V1A blockade in the treatment of patients with elevated levels of vasopressin.
authors: Center For Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia, PA 19107, USA.
authors: Xue
authors: X
authors: Li
authors: Tung O
authors: TO
authors: Chan
authors: Valerie
authors: V
authors: Myers
authors: Ibrul
authors: I
authors: Chowdhury
authors: Xue-Qian
authors: XQ
authors: Zhang
authors: Jianliang
authors: J
authors: Song
authors: Jin
authors: J
authors: Zhang
authors: Jocelyn
authors: J
authors: Andrel
authors: Hajime
authors: H
authors: Funakoshi
authors: Jeffrey
authors: J
authors: Robbins
authors: Walter J
authors: WJ
authors: Koch
authors: Terry
authors: T
authors: Hyslop
authors: Joseph Y
authors: JY
authors: Cheung
authors: Arthur M
authors: AM
authors: Feldman
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017483:Receptors, Vasopressin / Q000235:genetics*; D018487:Ventricular Dysfunction, Left / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D007328:Insulin; D017483:Receptors, Vasopressin; D048049:Extracellular Signal-Regulated MAP Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium