title: Endogenous regulation of cardiovascular function by apelin-APJ.
abstract: Studies have shown significant cardiovascular effects of exogenous apelin administration, including the potent activation of cardiac contraction. However, the role of the endogenous apelin-APJ pathway is less clear. To study the loss of endogenous apelin-APJ signaling, we generated mice lacking either the ligand (apelin) or the receptor (APJ). Apelin-deficient mice were viable, fertile, and showed normal development. In contrast, APJ-deficient mice were not born in the expected Mendelian ratio, and many showed cardiovascular developmental defects. Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. However, with exercise stress both mutant lines demonstrated consistent and striking decreases in exercise capacity. To explain these findings, we explored the role of autocrine signaling in vitro using field stimulation of isolated left ventricular cardiomyocytes lacking either apelin or APJ. Both groups manifested less sarcomeric shortening and impaired velocity of contraction and relaxation with no difference in calcium transient. Taken together, these results demonstrate that endogenous apelin-APJ signaling plays a modest role in maintaining basal cardiac function in adult mice with a more substantive role during conditions of stress. In addition, an autocrine pathway seems to exist in myocardial cells, the ablation of which reduces cellular contraction without change in calcium transient. Finally, differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ.
authors.affiliation: Department of Medicine (Cardiovascular Medicine), Stanford University, Stanford, CA 94305, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Charo
authors.forename: Michael
authors.initials: M
authors.lastname: Ho
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fajardo
authors.forename: Masataka
authors.initials: M
authors.lastname: Kawana
authors.forename: Ramendra K
authors.initials: RK
authors.lastname: Kundu
authors.forename: Ahmad Y
authors.initials: AY
authors.lastname: Sheikh
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Finsterbach
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Leeper
authors.forename: Kavita V
authors.initials: KV
authors.lastname: Ernst
authors.forename: Mary M
authors.initials: MM
authors.lastname: Chen
authors.forename: Yen Dong
authors.initials: YD
authors.lastname: Ho
authors.forename: Hyung J
authors.initials: HJ
authors.lastname: Chun
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.forename: Euan A
authors.initials: EA
authors.lastname: Ashley
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
mesh_terms: D054392:Adipokines; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D019898:Autocrine Communication; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D017079:Exercise Tolerance / Q000235:genetics; D005260:Female; D005838:Genotype; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012518:Sarcomeres / Q000378:metabolism; D013318:Stroke Volume; D016276:Ventricular Function; D017725:Ventricular Pressure
chemical_list: D054392:Adipokines; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled