This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 104/9/1076    most recent CIRCRESAHA.109.196899v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lombardi, R. Articles by Marian, A. J. Search for Related Content PubMed PubMed Citation Articles by Lombardi, R. Articles by Marian, A. J. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Cardiomyopathy Stem Cells Related Collections Other heart failure Animal models of human disease Myogenesis Cardiac development

(Circulation Research. 2009;104:1076.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Genetic Fate Mapping Identifies Second Heart Field Progenitor Cells As a Source of Adipocytes in Arrhythmogenic Right Ventricular Cardiomyopathy

Raffaella Lombardi, Jinjiang Dong, Gabriela Rodriguez, Achim Bell, Tack Ki Leung, Robert J. Schwartz, James T. Willerson, Ramon Brugada, Ali J. Marian

From the Center for Cardiovascular Genetics (R.L., J.D., G.R., A.B., J.T.W., A.J.M.), Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center and Texas Heart Institute, Houston; Montreal Heart Institute and Université de Montréal (T.K.L., R.B.), Quebec, Canada; and Institute of Biotechnology (R.J.S.), Texas A&M University, Houston.

Correspondence to A. J. Marian, MD, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Sciences Center, 6770 Bertner St, Suite C900A, Houston, TX 77030. E-mail Ali.J.Marian{at}uth.tmc.edu

The phenotypic hallmark of arrhythmogenic right ventricular cardiomyopathy, a genetic disease of desmosomal proteins, is fibroadipocytic replacement of the right ventricle. Cellular origin of excess adipocytes, the responsible mechanism(s) and the basis for predominant involvement of the right ventricle are unknown. We generated 3 sets of lineage tracer mice regulated by cardiac lineage promoters -myosin heavy chain (MyHC), Nkx2.5, or Mef2C. We conditionally expressed the reporter enhanced yellow fluorescent protein while concomitantly deleting the desmosomal protein desmoplakin in cardiac myocyte lineages using the Cre-LoxP technique. Lineage tracer mice showed excess fibroadiposis and increased numbers of adipocytes in the hearts. Few adipocytes in the hearts of MyHC-regulated lineage tracer mice, but the majority of adipocytes in the hearts of Nkx2.5- and Mef2C-regulated lineage tracer mice, expressed enhanced yellow fluorescent protein. In addition, rare cells coexpressed adipogenic transcription factors and the second heart field markers Isl1 and Mef2C in the lineage tracer mouse hearts and in human myocardium from patients with arrhythmogenic right ventricular cardiomyopathy. To delineate the responsible mechanism, we generated transgenic mice expressing desmosomal protein plakoglobin in myocyte lineages. Transgene plakoglobin translocated to nucleus, detected by immunoblotting and immunofluorescence staining and coimmunoprecipitated with Tcf7l2, a canonical Wnt signaling transcription factor. Expression levels of canonical Wnt/Tcf7l2 targets bone morphogenetic protein 7 and Wnt5b, which promote adipogenesis, were increased and expression level of connective tissue growth factor, an inhibitor of adipogenesis, was decreased. We conclude adipocytes in arrhythmogenic right ventricular cardiomyopathy originate from the second heart field cardiac progenitors, which switch to an adipogenic fate because of suppressed canonical Wnt signaling by nuclear plakoglobin.

Key Words: adipocytes • progenitor cells • Wnt signaling • desmosomes • heart failure