RXRα overexpression in cardiomyocytes causes dilated cardiomyopathy but fails to rescue myocardial hypoplasia in RXRα-null fetuses
Vemparala Subbarayan, … , Pierre Chambon, Philippe Kastner
Vemparala Subbarayan, … , Pierre Chambon, Philippe Kastner
Published February 1, 2000
Citation Information: J Clin Invest. 2000;105(3):387-394. https://doi.org/10.1172/JCI8150.
View: Text | PDF
Article

RXRα overexpression in cardiomyocytes causes dilated cardiomyopathy but fails to rescue myocardial hypoplasia in RXRα-null fetuses

Abstract

Retinoid X receptor α–null (RXRα-null) mutants exhibit hypoplasia of their ventricular myocardium and die at the fetal stage. In the present study, we wished to determine whether transgenic re-expression of RXRα in mutant cardiac myocytes could rescue these defects. Two transgenic mouse lines specifically overexpressing an RXRα protein in cardiomyocytes were generated, using the cardiac α-myosin heavy chain (α-MHC) promoter. Breeding the high copy number transgenic line onto an RXRα-null genetic background did not prevent the myocardial hypoplasia and fetal lethality associated with the RXRα–/– genotype, even though the transgene was expressed in the ventricles as early as 10.5 days post-coitum. These data suggest that the RXRα function involved in myocardial growth may correspond to a non–cell-autonomous requirement forsignal orchestrating the growth and differentiation of myocytes. Interestingly, the adult transgenic mice developed a dilated cardiomyopathy, associated with myofibrillar abnormalities and specific deficiencies in respiratory chain complexes I and II, thus providing an additional model for this genetically complex disease.

Authors

Vemparala Subbarayan, Manuel Mark, Nadia Messadeq, Pierre Rustin, Pierre Chambon, Philippe Kastner

×

Figure 4

Options: View larger image (or click on image) Download as PowerPoint
DCM in mice from line 41. (a) Increased lethality of heterozygous mice f...
DCM in mice from line 41. (a) Increased lethality of heterozygous mice from line 41. Mice were subdivided within 3 age groups, and the percentages of deaths occurring within the corresponding life periods are indicated. WT mice were the littermates of the transgenic ones. (b–e) Cardiac dilation in heterozygous transgenic mice from line 41. External views of the hearts from a WT mouse and of a dilated heart from a transgenic littermate (TG) (2 months old) are shown in b and c, and transverse sections through the same hearts, in d and e. Note that the transgenic mouse from which the heart was taken displayed obvious signs of weakness. All the chambers of the transgenic heart contained organized thrombi that were removed during dissection, except one in the atrium (large arrow). A, atria; V, ventricles; VS, ventricular septum; LV, left ventricle; RV, right ventricle.