Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodelling

Abstract

Aims Pathological cardiac remodeling is characterized by cardiomyocyte hypertrophy and fibroblast activation, which can ultimately lead to maladaptive hypertrophy and heart failure (HF). Genome-wide expression analysis on heart tissue has been instrumental for the identification of molecular mechanisms at play. However, these data were based on signals derived from all cardiac cell types. Here we aimed for a more detailed view on molecular changes driving maladaptive cardiomyocyte hypertrophy to aid in the development of therapies to reverse pathological remodeling. Methods and Results Utilizing cardiomyocyte-specific reporter mice exposed to pressure overload by transverse aortic banding and cardiomyocyte isolation by flow cytometry, we obtained gene expression profiles of hypertrophic cardiomyocytes in the more immediate phase after stress, and cardiomyocytes showing pathological hypertrophy. We identified subsets of genes differentially regulated and specific for either stage. Among the genes specifically upregulated in the cardiomyocytes during the maladaptive phase we found known stress markers, such as Nppb and Myh7, but additionally identified a set of genes with unknown roles in pathological hypertrophy, including the platelet isoform of phosphofructokinase (PFKP). Norepinephrine-angiotensin II treatment of cultured human cardiomyocytes induced secretion of NT pro-BNP and recapitulated the upregulation of these genes, indicating conservation of the upregulation in failing cardiomyocytes. Moreover, several genes induced during pathological hypertrophy were also found to be increased in human heart failure, with their expression positively correlating to the known stress markers NPPB and MYH7. Mechanistically, suppression of Pfkp in primary cardiomyocytes attenuated stress-induced gene expression and hypertrophy, indicating that Pfkp is an important novel player in pathological remodeling of cardiomyocytes. Conclusions Using cardiomyocyte-specific transcriptomic analysis we identified novel genes induced during pathological hypertrophy that are relevant for human HF, and we show that PFKP is a conserved failure-induced gene that can modulate the cardiomyocyte stress response. Translational perspective Maladaptive cardiac remodeling is a consequence of pathological hypertrophy which includes cardiomyocytes changes and a decline in contractility. Our cardiomyocyte-specific gene expression studies revealed a gene program specific for pathological hypertrophy that is conserved in diseased mouse and human cardiomyocytes. We identified PFKP as a novel gene actively involved in cardiomyocyte remodeling, indicating PFKP as a potential therapeutic target to block the progression of heart failure.

Differences in molecular phenotype in mouse and human hypertrophic cardiomyopathy

“…7 c,e; 8 a,e; Supplemental Tables 6 – 7 ). The most dysregulated gene in myectomy tissue was RASL11B 58 (log2FC 1.72), which has been associated with pathologic cardiac hypertrophy 58 in mice and humans.…”

Lineage-specific regulatory changes in the pathological cardiac remodeling of hypertrophy cardiomyopathy unraveled by single-nucleus RNA-seq and spatial transcriptomics

“…Pathological cardiac hypertrophy is a common predecessor to heart failure. 35 A recent study reported the transcriptomic differences of cardiomyocytes between early (hypertrophic cardiomyocytes) and maladaptive phage (failing cardiomyocytes) of cardiac remodeling in pressure overload-induced mouse models, 36 Through pseudo-temporal ordering, we identified the transcriptomic dynamics during the transition towards the failing state of cardiomyocytes in HCM of human patients (Figure 2I). Based on multiple lines of evidence from independent analyses, we obtained a list of genes that could serve as potential medical targets for mitigating the progression of heart failure in HCM (Figure 2J), and most have not been implicated in heart failure or cardiac hypertrophy such as FGF12 , IL31RA , BDNF and PROS1 .…”

Knockout of Sorbs2 in Cardiomyocytes Leads to Dilated Cardiomyopathy in Mice

“…Our interrogation of independent RNA expression data and western blot data shows consistent upregulation in Sorbs2 across a range of myocardial diseases, as has been recently noted. 73 Further, Sorbs2 protein is upregulated in LVNC, 8 diabetic cardiomyopathy, 6 and is released from infarcted myocardium. 4 Upregulation is potentially mediated by Mef2 transcription factors, 74 although posttranscriptional regulation by disease-relevant microRNAs and RNA-binding proteins may also contribute.…”