Cpxm2 as a novel candidate for cardiac hypertrophy and failure in hypertension

Katja Grabowski,Laura Herlan,Anika Witten,Felicitas Escher,Michael Bader,Ketaki Nitin Mhatre,Monika Stoll,Fatimunnisa Qadri,Dirk Westermann,Jana Subrova,Sophie Van Linthout,Martin Schädlich,Frank R Heinzel,Ralph Plehm,Andreas Eisenreich,Uwe Primessnig,Reinhold Kreutz,Diana Lindner,Angela Schulz

doi:10.1038/s41440-021-00826-8

Abstract

Treatment of hypertension-mediated cardiac damage with left ventricular (LV) hypertrophy (LVH) and heart failure remains challenging. To identify novel targets, we performed comparative transcriptome analysis between genetic models derived from stroke-prone spontaneously hypertensive rats (SHRSP). Here, we identified carboxypeptidase X 2 (Cpxm2) as a genetic locus affecting LV mass. Analysis of isolated rat cardiomyocytes and cardiofibroblasts indicated Cpxm2 expression and intrinsic upregulation in genetic hypertension. Immunostaining indicated that CPXM2 associates with the t-tubule network of cardiomyocytes. The functional role of Cpxm2 was further investigated in Cpxm2-deficient (KO) and wild-type (WT) mice exposed to deoxycorticosterone acetate (DOCA). WT and KO animals developed severe and similar systolic hypertension in response to DOCA. WT mice developed severe LV damage, including increases in LV masses and diameters, impairment of LV systolic and diastolic function and reduced ejection fraction. These changes were significantly ameliorated or even normalized (i.e., ejection fraction) in KO-DOCA animals. LV transcriptome analysis showed a molecular cardiac hypertrophy/remodeling signature in WT but not KO mice with significant upregulation of 1234 transcripts, including Cpxm2, in response to DOCA. Analysis of endomyocardial biopsies from patients with cardiac hypertrophy indicated significant upregulation of CPXM2 expression. These data support further translational investigation of CPXM2.

Highlights

MethodsHypertension-mediated organ damage (HMOD), including cardiac hypertrophy, has a major impact on the morbidity and mortality of hypertensive patients [1, 2]
Transcriptome analysis in hypertensive rat models identifies Cpxm2 as a novel molecule related to LV hypertrophy (LVH)
We subsequently focused on mRNAs that were differentially expressed between the SHRSP and consomic SHSRP-1F344 strains (Fig. 1a and Supplementary Table 3) because both strains share the same genetic background, while RNO1 carries the LVH quantitative trait locus (QTL)

Summary

Methods

Hypertension-mediated organ damage (HMOD), including cardiac hypertrophy, has a major impact on the morbidity and mortality of hypertensive patients [1, 2]. At 12 weeks of age, unilateral nephrectomy was performed under anesthesia (isoflurane 3.5% induction followed by 1.5% maintenance dose) in WT and KO mice (n = 8/group), and a pellet containing DOCA was implanted in each mouse subcutaneously (DOCA pellet, 75 mg, 60-day release, Innovative Research of America, Sarasota, Florida, USA). These mice were exposed to salt by adding 1% NaCl to drinking water (DOCA groups). We used IBM SPSS Statistics 22 for statistical analysis, GraphPad Prism and OriginLab 8.1 G for graph preparation (GraphPad Prism version 8.0 for Windows, GraphPad Software, La Jolla California USA, www.graphpad.com; OriginLab Corporation, Northampton, MA, USA)

Results

Discussion

Compliance with ethical standards