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No Contribution of IP3-R(2) to Disease Phenotype in Models of Dilated Cardiomyopathy or Pressure Overload Hypertrophy.
- Source :
- Circulation: Heart Failure; Mar2013, Vol. 6 Issue 2, p318-325, 8p
- Publication Year :
- 2013
-
Abstract
- We investigated the contribution of inositol(1,4,5)-trisphosphate (Ins(1,4,5)P<subscript>3</subscript> [IP<subscript>3</subscript>]) receptors (IP<subscript>3</subscript>-R) to disease progression in mouse models of dilated cardiomyopathy (DCM) and pressure overload hypertrophy. Mice expressing mammalian sterile 20-like kinase and dominant-negative phosphatidylinositol-3-kinase in heart (Mst1×dn-PI3K-2Tg; DCM-2Tg) develop severe DCM and conduction block, associated with increased expression of type 2 IP<subscript>3</subscript>-R (IP<subscript>3</subscript>-R(2)) and heightened generation of Ins(1,4,5)P<subscript>3</subscript>. Similar increases in Ins(1,4,5)P<subscript>3</subscript> and IP<subscript>3</subscript>-R(2) are caused by transverse aortic constriction.To evaluate the contribution of IP<subscript>3</subscript>-R(2) to disease progression, the DCM-2Tg mice were further crossed with mice in which the type 2 IP<subscript>3</subscript>-R (IP<subscript>3</subscript>-R(2)-/-) had been deleted (DCM-2Tg×IP<subscript>3</subscript>-R(2)-/-) and transverse aortic constriction was performed on IP<subscript>3</subscript>-R(2)-/- mice. Hearts from DCM-2Tg mice and DCM-2Tg×IP<subscript>3</subscript>-R(2)-/- were similar in terms of chamber dilatation, atrial enlargement, and ventricular wall thinning. Electrophysiological changes were also similar in the DCM-2Tg mice, with and without IP<subscript>3</subscript>-R(2). Deletion of IP<subscript>3</subscript>-R(2) did not alter the progression of heart failure, because DCM-2Tg mice with and without IP<subscript>3</subscript>-R(2) had similarly reduced contractility, increased lung congestion, and atrial thrombus, and both strains died between 10 and 12 weeks of age. Loss of IP<subscript>3</subscript>-R(2) did not alter the progression of hypertrophy after transverse aortic constriction.We conclude that IP<subscript>3</subscript>-R(2) do not contribute to the progression of DCM or pressure overload hypertrophy, despite increased expression and heightened generation of the ligand, Ins(1,4,5)P<subscript>3</subscript>. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19413289
- Volume :
- 6
- Issue :
- 2
- Database :
- Supplemental Index
- Journal :
- Circulation: Heart Failure
- Publication Type :
- Academic Journal
- Accession number :
- 110241767
- Full Text :
- https://doi.org/10.1161/CIRCHEARTFAILURE.112.972158