In vivo genetic profiling and cellular localization of apelin reveals a hypoxia-sensitive, endothelial-centered pathway activated in ischemic heart failure

Autor: Ingo Kutschka, Ziad A. Ali, Philip S. Tsao, Stephen L. Hendry, Mary M. Chen, Patrick Yue, Diego Ardigò, Ramendera K. Kundu, Marc P. Pelletier, Hyung J. Chun, Robert C. Robbins, Andrew J. Connolly, Ahmad Y. Sheikh, Alexander J. Glassford, Thomas Quertermous, Roger A. Wagner, Diem T. Huynh
Rok vydání: 2008
Předmět:
Time Factors
Physiology
Myocardial Ischemia
Quadriceps Muscle
Receptors
G-Protein-Coupled
Mice
Genes
Reporter
Basic Helix-Loop-Helix Transcription Factors
Hypoxia
Promoter Regions
Genetic
Lung
Cells
Cultured
Cellular localization
Apelin Receptors
Coronary Vessels
Cell Hypoxia
Up-Regulation
Apelin
Cell biology
medicine.anatomical_structure
Lac Operon
Intercellular Signaling Peptides and Proteins
Female
medicine.symptom
Signal transduction
Cardiology and Cardiovascular Medicine
Signal Transduction
medicine.medical_specialty
Endothelium
Mice
Transgenic
Biology
Transfection
Article
Adipokines
Physiology (medical)
Internal medicine
Renin–angiotensin system
medicine
Animals
Humans
RNA
Messenger
Ligation
Apelin receptor
Heart Failure
Gene Expression Profiling
Myocardium
Endothelial Cells
Hypoxia (medical)
Hypoxia-Inducible Factor 1
alpha Subunit
medicine.disease
Disease Models
Animal
Endocrinology
Heart failure
Carrier Proteins
Zdroj: American Journal of Physiology-Heart and Circulatory Physiology. 294:H88-H98
ISSN: 1522-1539
0363-6135
DOI: 10.1152/ajpheart.00935.2007
Popis: Signaling by the peptide ligand apelin and its cognate G protein-coupled receptor APJ has a potent inotropic effect on cardiac contractility and modulates systemic vascular resistance through nitric oxide-dependent signaling. In addition, there is evidence for counterregulation of the angiotensin and vasopressin pathways. Regulatory stimuli of the apelin-APJ pathway are of obvious importance but remain to be elucidated. To better understand the physiological response of apelin-APJ to disease states such as heart failure and to elucidate the mechanism by which such a response might occur, we have used the murine model of left anterior descending coronary artery ligation-induced ischemic cardiac failure. To identify the key cells responsible for modulation and production of apelin in vivo, we have created a novel apelin-lacZ reporter mouse. Data from these studies demonstrate that apelin and APJ are upregulated in the heart and skeletal muscle following myocardial injury and suggest that apelin expression remains restricted to the endothelium. In cardiac failure, endothelial apelin expression correlates with other hypoxia-responsive genes, and in healthy animals both apelin and APJ are markedly upregulated in various tissues following systemic hypoxic exposure. Experiments with cultured endothelial cells in vitro show apelin mRNA and protein levels to be increased by hypoxia, through a hypoxia-inducible factor-mediated pathway. These studies suggest that apelin-expressing endothelial cells respond to conditions associated with heart failure, possibly including local tissue hypoxia, and modulate apelin-APJ expression to regulate cardiovascular homeostasis. The apelin-APJ pathway may thus provide a mechanism for systemic endothelial monitoring of tissue perfusion and adaptive regulation of cardiovascular function.
Databáze: OpenAIRE
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