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

TY - JOUR

T1 - Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodeling

AU - Vigil-Garcia, Marta

AU - Demkes, Charlotte J

AU - Eding, Joep E C

AU - Versteeg, Danielle

AU - de Ruiter, Hesther

AU - Perini, Ilaria

AU - Kooijman, Lieneke

AU - Gladka, Monika M

AU - Asselbergs, Folkert W

AU - Vink, Aryan

AU - Harakalova, Magdalena

AU - Bossu, Alexander

AU - van Veen, Toon A B

AU - Boogerd, Cornelis J

AU - van Rooij, Eva

N1 - © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2020/7/27

Y1 - 2020/7/27

N2 - 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.

AB - 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.

U2 - 10.1093/cvr/cvaa233

DO - 10.1093/cvr/cvaa233

M3 - Article

C2 - 32717063

SN - 0008-6363

JO - Cardiovascular Research

JF - Cardiovascular Research

ER -