Cpxm2 as a novel candidate for cardiac hypertrophy and failure in hypertension
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Cpxm2 as a novel candidate for cardiac hypertrophy and failure in hypertension. / Grabowski, Katja; Herlan, Laura; Witten, Anika; Qadri, Fatimunnisa; Eisenreich, Andreas; Lindner, Diana; Schädlich, Martin; Schulz, Angela; Subrova, Jana; Mhatre, Ketaki Nitin; Primessnig, Uwe; Plehm, Ralph; van Linthout, Sophie; Escher, Felicitas; Bader, Michael; Stoll, Monika; Westermann, Dirk; Heinzel, Frank R; Kreutz, Reinhold.
in: HYPERTENS RES, Jahrgang 45, Nr. 2, 02.2022, S. 292-307.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Cpxm2 as a novel candidate for cardiac hypertrophy and failure in hypertension
AU - Grabowski, Katja
AU - Herlan, Laura
AU - Witten, Anika
AU - Qadri, Fatimunnisa
AU - Eisenreich, Andreas
AU - Lindner, Diana
AU - Schädlich, Martin
AU - Schulz, Angela
AU - Subrova, Jana
AU - Mhatre, Ketaki Nitin
AU - Primessnig, Uwe
AU - Plehm, Ralph
AU - van Linthout, Sophie
AU - Escher, Felicitas
AU - Bader, Michael
AU - Stoll, Monika
AU - Westermann, Dirk
AU - Heinzel, Frank R
AU - Kreutz, Reinhold
N1 - © 2021. The Author(s).
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
KW - Animals
KW - Carboxypeptidases
KW - Cardiomegaly/genetics
KW - Humans
KW - Hypertension
KW - Hypertrophy, Left Ventricular
KW - Mice
KW - Myocytes, Cardiac
KW - Rats
U2 - 10.1038/s41440-021-00826-8
DO - 10.1038/s41440-021-00826-8
M3 - SCORING: Journal article
C2 - 34916661
VL - 45
SP - 292
EP - 307
JO - HYPERTENS RES
JF - HYPERTENS RES
SN - 0916-9636
IS - 2
ER -