1. Cpxm2 as a novel candidate for cardiac hypertrophy and failure in hypertension
- Author
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Katja Grabowski, Laura Herlan, Anika Witten, Fatimunnisa Qadri, Andreas Eisenreich, Diana Lindner, Martin Schädlich, Angela Schulz, Jana Subrova, Ketaki Nitin Mhatre, Uwe Primessnig, Ralph Plehm, Sophie van Linthout, Felicitas Escher, Michael Bader, Monika Stoll, Dirk Westermann, Frank R. Heinzel, Reinhold Kreutz, Biochemie, RS: FHML MaCSBio, and RS: Carim - B01 Blood proteins & engineering
- Subjects
Physiology ,LOCI ,Cardiomegaly ,Carboxypeptidases ,Article ,Mice ,LEFT-VENTRICULAR MASS ,Cpxm2 ,Internal Medicine ,Genetics ,Animals ,Humans ,Myocytes, Cardiac ,Knock-out mice ,GENE-EXPRESSION ,IDENTIFICATION ,DOCA-salt hypertension ,EUROPEAN-SOCIETY ,DYSFUNCTION ,Rats ,Cardiac hypertrophy ,CARBOXYPEPTIDASE-LIKE PROTEIN ,PRESERVED EJECTION FRACTION ,Cardiovascular and Metabolic Diseases ,Hypertension ,HEART-FAILURE ,Hypertrophy, Left Ventricular ,Cardiology and Cardiovascular Medicine ,TASK-FORCE - 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., Differential increased cardiac expression of Cpxm2 was assigned to cardiac hypertrophy in SHRSP rats. Cpxm2 knock-out (KO) in mice reduced cardiac hypertrophy and remodeling in DOCA salt hypertension
- Published
- 2021