Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload

Keiji Kuba, Liyong Zhang, Yumiko Imai, Sara Arab, Manyin Chen, Yuichiro Maekawa, Michael Leschnik, Andreas Leibbrandt, Mato Makovic, Julia Schwaighofer, Nadine Beetz, Renata Musialek, G. Greg Neely, Vukoslav Komnenovic, Ursula Kolm, Bernhard Metzler, Romeo Ricci, Hiromitsu Hara, Arabella Meixner, Mai NghiemXin Chen, Fayez Dawood, Kit Man Wong, Renu Sarao, Eva Cukerman, Akinori Kimura, Lutz Hein, Johann Thalhammer, Peter P. Liu, Josef M. Penninger

Research output: Contribution to journalArticlepeer-review

202 Citations (Scopus)

Abstract

Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene-targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload-induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin and Apelin mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.

Original languageEnglish
Pages (from-to)e32-e42
JournalCirculation research
Volume101
Issue number4
DOIs
Publication statusPublished - 2007 Aug

Keywords

  • Aging
  • Angiotensin
  • Cardiac failure
  • Cardiac function
  • Pressure overload

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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