Molecular profiling of dilated cardiomyopathy that progresses to heart failure
Michael A. Burke, Stephen Chang, Hiroko Wakimoto, Joshua M. Gorham, David A. Conner, Danos C. Christodoulou, Michael G. Parfenov, Steve R. DePalma, Seda Eminaga, Tetsuo Konno, Jonathan G. Seidman, Christine E. Seidman
Michael A. Burke, Stephen Chang, Hiroko Wakimoto, Joshua M. Gorham, David A. Conner, Danos C. Christodoulou, Michael G. Parfenov, Steve R. DePalma, Seda Eminaga, Tetsuo Konno, Jonathan G. Seidman, Christine E. Seidman
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Research Article Cardiology

Molecular profiling of dilated cardiomyopathy that progresses to heart failure

Abstract

Dilated cardiomyopathy (DCM) is defined by progressive functional and structural changes. We performed RNA-seq at different stages of disease to define molecular signaling in the progression from pre-DCM hearts to DCM and overt heart failure (HF) using a genetic model of DCM (phospholamban missense mutation, PLNR9C/+). Pre-DCM hearts were phenotypically normal yet displayed proliferation of nonmyocytes (59% relative increase vs. WT, P = 8 × 10–4) and activation of proinflammatory signaling with notable cardiomyocyte-specific induction of a subset of profibrotic cytokines including TGFβ2 and TGFβ3. These changes progressed through DCM and HF, resulting in substantial fibrosis (17.6% of left ventricle [LV] vs. WT, P = 6 × 10–33). Cardiomyocytes displayed a marked shift in metabolic gene transcription: downregulation of aerobic respiration and subsequent upregulation of glucose utilization, changes coincident with attenuated expression of PPARα and PPARγ coactivators -1α (PGC1α) and -1β, and increased expression of the metabolic regulator T-box transcription factor 15 (Tbx15). Comparing DCM transcriptional profiles with those in hypertrophic cardiomyopathy (HCM) revealed similar and distinct molecular mechanisms. Our data suggest that cardiomyocyte-specific cytokine expression, early fibroblast activation, and the shift in metabolic gene expression are hallmarks of cardiomyopathy progression. Notably, key components of these profibrotic and metabolic networks were disease specific and distinguish DCM from HCM.

Authors

Michael A. Burke, Stephen Chang, Hiroko Wakimoto, Joshua M. Gorham, David A. Conner, Danos C. Christodoulou, Michael G. Parfenov, Steve R. DePalma, Seda Eminaga, Tetsuo Konno, Jonathan G. Seidman, Christine E. Seidman

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Figure 4

Increased expression of TGFβ in PLNR9C/+ mice.

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Increased expression of TGFβ in PLNR9C/+ mice. (A) All TGFβ isoforms wer...
(A) All TGFβ isoforms were predicted to be activated at all 3 stages of disease by upstream regulator analysis. Z-score reflects both the confidence and direction of the inferred activation state (P < 1 × 10–6 for all analyses). (B) TGFβ gene expression was induced in PLNR9C/+ LV tissue at all stages of disease (n = 3 mice pooled prior to RNA-seq). (C) Isolated nonmyocyte and cardiomyocyte cells (n = 6 mice pooled prior to RNA-seq) at 18 weeks (DCM) showed that TGFβ genes were predominantly expressed in WT nonmyocytes, with modest increases in Tgfb2 and Tgfb3 expression in PLNR9C/+ nonmyocytes. In contrast, Tgfb2 and Tgfb3 were strongly induced in cardiomyocytes of PLNR9C/+ mice with DCM. Tgfb1 levels do not change significantly in either cell compartment. Bayesian P value corrected for multiple hypothesis testing (10).