Abstract
Rationale: With a prevalence of 1 in 200 individuals, hypertrophic cardiomyopathy (HCM) is thought to be the most common genetic cardiac disease, with potential outcomes that include severe hypertrophy, heart failure, and sudden cardiac death (SCD). Though much research has furthered our understanding of how HCM-causing mutations in genes such as cardiac myosin-binding protein C (MYBPC3) impair contractile function, it remains unclear how such dysfunction leads to hypertrophy and/or arrhythmias, which comprise the HCM phenotype. Identification of early response mediators could provide rational therapeutic targets to reduce disease severity. Our goal was to differentiate physiologic and pathophysiologic hypertrophic growth responses and identify early genetic mediators in the development of cardiomegaly in the cardiac myosin-binding protein C-null (cMyBP-C-/-) mouse model of HCM.Methods and Results: We performed microarray analysis on left ventricles of wild-type (WT) and cMyBPC-/- mice (n = 7 each) at postnatal day (PND) 1 and PND 9, before and after the appearance of an overt HCM phenotype. Applying the criteria of ≥2-fold change, we identified genes whose change was exclusive to pathophysiologic growth (n = 61), physiologic growth (n = 30), and genes whose expression changed ≥2-fold in both WT and cMyBP-C-/- hearts (n = 130). Furthermore, we identified genes that were dysregulated in PND1 cMyBP-C-/- hearts prior to hypertrophy, including genes in mechanosensing pathways and potassium channels linked to arrhythmias. One gene of interest, Xirp2, and its protein product, are regulated during growth but also show early, robust prehypertrophic upregulation in cMyBP-C-/- hearts. Additionally, the transcription factor Zbtb16 also shows prehypertrophic upregulation at both gene and protein levels.Conclusion: Our transcriptome analysis generated a comprehensive data set comparing physiologic vs. hypertrophic growth in mice lacking cMyBP-C. It highlights the importance of extracellular matrix pathways in hypertrophic growth and early dysregulation of potassium channels. Prehypertrophic upregulation of Xirp2 in cMyBP-C-/- hearts supports a growing body of evidence suggesting Xirp2 has the capacity to elicit both hypertrophy and arrhythmias in HCM. Dysregulation of Xirp2, as well as Zbtb16, along with other genes associated with mechanosensing regions of the cardiomyocyte implicate stress-sensing in these regions as a potentially important early response in HCM.
Highlights
Hypertrophic cardiomyopathy (HCM), thought to be the leading genetic cardiovascular disease (Semsarian et al, 2015), is characterized by hypertrophy of the left ventricular free wall and septum and can be accompanied by myocardial disarray, diastolic dysfunction, and fibrosis (Fananapazir and Epstein, 1994; Davies and McKenna, 1995)
We performed microarray analysis using RNA isolated from left ventricular free walls from cardiac myosin-binding protein C (cMyBP-C)−/− and WT mice at PND1 and PND9 to highlight differential RNA expression before and after the presentation of overt hypertrophy and dysfunction, and to uncover cell signaling that might influence the differential pathways leading to physiologic growth vs. pathologic hypertrophy
Microarray analysis revealed that 30 genes were exclusively regulated during physiologic growth (WT PND1-PND9; Supplementary Table S1), 61 genes were exclusively regulated during hypertrophic growth, and 130 genes were common to both physiologic and hypertrophic growth (Supplementary Table S3), represented by the intersection of two circles of a Venn diagram (Figure 1)
Summary
Hypertrophic cardiomyopathy (HCM), thought to be the leading genetic cardiovascular disease (Semsarian et al, 2015), is characterized by hypertrophy of the left ventricular free wall and septum and can be accompanied by myocardial disarray, diastolic dysfunction, and fibrosis (Fananapazir and Epstein, 1994; Davies and McKenna, 1995). Genes encoding the sarcomeric proteins β-myosin heavy chain (β-MHC) and cardiac myosin-binding protein C (cMyBP-C) harbor the majority of HCM-causing mutations in this autosomal dominant disease (Richard et al, 2003; Olivotto et al, 2008; Alfares et al, 2015). The majority of mutations in the MYBPC3 gene lead to decreased levels of functional cMyBP-C and, in animal models, result in accelerated sarcomere cross-bridge cycling and increased contractile kinetics. Our initial analysis of the microarray data focused on global pathway alterations in the perinatal, pre-hypertrophic cMyBP-C−/− heart and revealed increased cardiomyocyte cell cycling and proliferation (Farrell et al, 2017). We distinguished gene expression programs involved in physiologic vs. pathophysiologic/hypertrophic growth
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