Abstract | BACKGROUND:
Apelin and its cognate G protein-coupled receptor, APJ, constitute a signaling pathway with a positive inotropic effect on cardiac function. Recently, we and other investigators demonstrated that a reduction in myocardial apelin/APJ expression might play a critical role in experimental models of end-stage heart failure (HF). Therefore, we evaluated whether exogenous apelin infusion restores apelin/APJ expression and improves cardiac function in the failing heart of Dahl salt-sensitive hypertensive (DS) rats. METHODS AND RESULTS: High salt-loaded DS rats were treated with vehicle and pyroglutamylated apelin-13 (Pyr-AP13; 200µg·kg(-1)·day(-1), IP) from the age of 11 to 18 weeks. Decreased end-systolic elastance and percent fractional shortening in failing rats was significantly ameliorated by Pyr-AP13. Pyr-AP13 effectively inhibited vascular lesion formation and suppressed expression of inflammation factors such as tumor necrosis factor-α and interleukin-1β protein. Downregulation of apelin and APJ expression, and phosphorylation of endothelial nitric oxide synthase at Ser(1177) and Akt at Ser(473) in failing rats was significantly increased by Pyr-AP13. Upregulation of NAD(P)H oxidase p22( phox), p47( phox), and gp91( phox) in DS rats was significantly suppressed by Pyr-AP13. CONCLUSIONS: Exogenous apelin-13 may ameliorate cardiac dysfunction and remodeling and restore apelin/APJ expression in DS rats with end-stage HF. Thus, apelin-13 may have significant therapeutic potential for end-stage HF.
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Authors | Wataru Koguchi, Naohiko Kobayashi, Hiroshi Takeshima, Mayuko Ishikawa, Fumihiro Sugiyama, Toshihiko Ishimitsu |
Journal | Circulation journal : official journal of the Japanese Circulation Society
(Circ J)
Vol. 76
Issue 1
Pg. 137-44
( 2012)
ISSN: 1347-4820 [Electronic] Japan |
PMID | 22082814
(Publication Type: Journal Article)
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Chemical References |
- Apelin Receptors
- Aplnr protein, rat
- Cardiotonic Agents
- Intercellular Signaling Peptides and Proteins
- Receptors, G-Protein-Coupled
- apelin-13 peptide
- Nitric Oxide Synthase Type III
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Topics |
- Animals
- Apelin Receptors
- Blood Pressure
(drug effects, physiology)
- Cardiotonic Agents
(pharmacology, therapeutic use)
- Disease Models, Animal
- Heart
(drug effects, physiopathology)
- Heart Failure
(drug therapy, physiopathology)
- Intercellular Signaling Peptides and Proteins
(pharmacology, physiology, therapeutic use)
- Male
- Nitric Oxide Synthase Type III
(metabolism)
- Phosphorylation
- Rats
- Rats, Inbred Dahl
- Receptors, G-Protein-Coupled
(physiology)
- Signal Transduction
(drug effects, physiology)
- Systole
(drug effects, physiology)
- Ventricular Remodeling
(drug effects, physiology)
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