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.

Global phosphoproteomic profiling reveals perturbed signaling in a mouse model of dilated cardiomyopathy

“…To identify disease signatures specifically relevant to DCM, we integrated and compared these pathways against a recent indepth RNA sequencing-based gene expression study of the R9C-PLN model (Datasets S2 and S7) (24). Specifically, differential mRNA expression modules in the Seidman study (24) corresponding to cardiomyocyte and nonmyocyte cardiac cell populations at different stages of disease (represented by six individual nodes) were tested for overlap with our enrichment map using a stringent MannWhitney test cutoff (P < 0.01).…”

“…Specifically, differential mRNA expression modules in the Seidman study (24) corresponding to cardiomyocyte and nonmyocyte cardiac cell populations at different stages of disease (represented by six individual nodes) were tested for overlap with our enrichment map using a stringent MannWhitney test cutoff (P < 0.01). Strikingly, we observed highly significant overlap between most of the disrupted biological processes and signaling pathways noted by the two studies, including (but not limited to) innate immunity, glucose metabolism, TGF-β signaling, PPAR signaling, Wnt/β-catenin signaling, and TLR signaling (Dataset S8).…”

“…Dilated cardiomyopathy, heart failure, diabetic cardiomyopathy (24,46) TLR signaling hsp90b1(s306), lgmn, ikbkb, map2k1, app, nfkb2(t425), dhx9(s137), dnm2, ppp2r5d,* unc93b1, dnm1(s774), itgb2, rps6ka3, eea1, dusp3, tlr3, ctsb, nfkb1, ube2n, ppp2ca, cd36, mef2a, ppp2r1a…”

“…Dilated cardiomyopathy, heart failure, ischemia-reperfusion, hypertrophy, viral myocarditis (24,47) Wnt signaling scyl2(s253), dab2ip(s854), ranbp3, cdh2, wwtr1,* rapgef1,* gsk3a, ppp2r3a, mcc,* dab2, limd1, ctnnb1, dact3(s165), bicc1, gsk3b, stk3(s246), ctnnd1(s813), g3bp1, cav1, ppp2r5a, pi4k2a(s462), cul3, mapk14,* dvl3,* hdac2(s394) Dilated cardiomyopathy, fibrosis, heart failure, myocardial infarction, arrhythmia (24,48) Phosphopeptides/proteins increased in R9C hearts are shown in bold, whereas components identified but showing a decrease in R9C are not bolded. The identified phosphorylation site of a particular protein is indicated in parentheses.…”

Exome Sequencing Identifies a Novel <b><i>DES</i></b> Mutation (R227C) in a Chinese Dilated Cardiomyopathy Family

“…115200) is the major cause of morbidity and mortality worldwide [1,2]. It is characterized by cardiac dilation and systolic dysfunction, and, in most patients, left ventricular enlargement or dilatation [3]. In the clinic, the symptoms of DCM include heart failure and are often related to sudden cardiac death [4].…”