Molecular profiling of dilated cardiomyopathy that progresses to heart failure
Michael A. Burke, … , Jonathan G. Seidman, Christine E. Seidman
Michael A. Burke, … , Jonathan G. Seidman, Christine E. Seidman
Published May 5, 2016
Citation Information: JCI Insight. 2016;1(6):e86898. https://doi.org/10.1172/jci.insight.86898.
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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 1

PLNR9C/+ mice develop increased cardiac fibrosis and nonmyocyte cell proliferation with disease progression.

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PLNR9C/+ mice develop increased cardiac fibrosis and nonmyocyte cell pro...
(A) Light microscopy (scale bars: 100 μm) of Masson’s trichrome–stained LV tissue at 8 weeks (pre-DCM), 18 weeks (DCM), and 22 weeks (overt HF) demonstrates progressive cardiac fibrosis in PLNR9C/+ hearts compared with age-matched WT animals. Data quantitated were individual LV slices (2 per slide) at 10 levels (apex to base) from n = 3 mice per group; 2-tailed Student’s t test. (B) Confocal microscopy (scale bars: 75 μm) and quantification of LV sections from hearts labeled with BrdU demonstrating nonmyocyte proliferation both pre-DCM and with overt HF. BrdU (magenta), wheat germ agglutinin (WGA; green), and nuclear DAPI (blue). Cells were counted from individual LV slices at 10 levels (apex to base) from n = 3 mice per group. Greater than 25,000 nuclei were counted per experiment; 2-tailed Student’s t test.