This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wold, L. E. Articles by Ren, J. Search for Related Content PubMed PubMed Citation Articles by Wold, L. E. Articles by Ren, J. Related Collections Animal models of human disease Calcium cycling/excitation-contraction coupling Cell signalling/signal transduction Hypertension - basic studies

(Hypertension. 2002;39:69.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Abrogated Leptin-Induced Cardiac Contractile Response in Ventricular Myocytes Under Spontaneous Hypertension

Role of JAK/STAT Pathway

Loren E. Wold; David P. Relling; Jinhong Duan; Faye L. Norby; Jun Ren

From the Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine, Grand Forks.

Correspondence to Dr. Jun Ren, Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine, 501 N. Columbia Road, Grand Forks, ND 58203. E-mail jren{at}medicine.nodak.edu

Leptin regulates cardiovascular function. Leptin levels are elevated in obesity and hypertension and may play a role in cardiovascular dysfunctions in these comorbidities. This study was designed to determine the influence of hypertension on the cardiac contractile response of leptin. Mechanical and intracellular Ca²⁺ properties were evaluated using an IonOptix system in ventricular myocytes from spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats. The contractile properties included peak shortening (PS), duration and maximal velocity of shortening/relengthening (TPS/TR₉₀, ±dL/dt), and fura-fluorescence intensity change (FFI). NO and nitric oxide synthase (NOS) activity were assessed by the Griess and the ³H-arginine/citrulline conversion assays, respectively. The leptin receptor (Ob-R) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were evaluated by Western blot analysis. SHR animals displayed significantly elevated blood pressure and plasma leptin levels. Leptin elicited a concentration-dependent inhibition of PS and FFI in WKY, but not in SHR myocytes. Leptin did not affect TPS, TR₉₀, or ± dL/dt. The difference in leptin-induced contractile response between the WKY and the SHR groups was abolished by the NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), but not by elevated extracellular Ca²⁺. Either the JAK2 inhibitor AG-490 or the mitogen-activated protein (MAP) kinase inhibitor SB203580 abrogated the leptin-induced response in the WKY myocytes, whereas AG-490 unmasked a negative response in PS in the SHR myocytes. SHR myocytes displayed similar Ob-R protein abundance and basal NO levels, a blunted leptin-induced increase in NOS activity as well as enhanced basal STAT3 levels compared with the WKY group. These data indicate that the leptin-induced cardiac contractile response is abolished by spontaneous hypertension, possibly because of mechanisms involving altered JAK/STAT, MAP kinase signaling, and NO response.

Key Words: signal transduction • hypertension, obesity • myocytes • cardiac function • kinase • nitric oxide

This article has been cited by other articles:

				R. Yang and L. A. Barouch Leptin Signaling and Obesity: Cardiovascular Consequences Circ. Res., September 14, 2007; 101(6): 545 - 559. [Abstract] [Full Text] [PDF]

				A. Rodriguez, A. Fortuno, J. Gomez-Ambrosi, G. Zalba, J. Diez, and G. Fruhbeck The Inhibitory Effect of Leptin on Angiotensin II-Induced Vasoconstriction in Vascular Smooth Muscle Cells Is Mediated via a Nitric Oxide-Dependent Mechanism Endocrinology, January 1, 2007; 148(1): 324 - 331. [Abstract] [Full Text] [PDF]

				H. Morawietz, S. R. Bornstein, F. Dong, X. Zhang, and J. Ren Leptin, Endothelin, NADPH Oxidase, and Heart Failure * Response: Leptin, Endothelin, NADPH Oxidase, and Heart Failure Hypertension, May 1, 2006; 47(5): e20 - e21. [Full Text] [PDF]

				F. Dong, X. Zhang, and J. Ren Leptin Regulates Cardiomyocyte Contractile Function Through Endothelin-1 Receptor-NADPH Oxidase Pathway Hypertension, February 1, 2006; 47(2): 222 - 229. [Abstract] [Full Text] [PDF]

				L. A. Barouch, D. Gao, L. Chen, K. L. Miller, W. Xu, A. C. Phan, M. M. Kittleson, K. M. Minhas, D. E. Berkowitz, C. Wei, et al. Cardiac Myocyte Apoptosis Is Associated With Increased DNA Damage and Decreased Survival in Murine Models of Obesity Circ. Res., January 6, 2006; 98(1): 119 - 124. [Abstract] [Full Text] [PDF]

				F Dong, X Zhang, X Yang, L B Esberg, H Yang, Z Zhang, B Culver, and J Ren Impaired cardiac contractile function in ventricular myocytes from leptin-deficient ob/ob obese mice J. Endocrinol., January 1, 2006; 188(1): 25 - 36. [Abstract] [Full Text] [PDF]

				L. Perego, P. Pizzocri, D. Corradi, F. Maisano, M. Paganelli, P. Fiorina, M. Barbieri, A. Morabito, G. Paolisso, F. Folli, et al. Circulating Leptin Correlates with Left Ventricular Mass in Morbid (Grade III) Obesity before and after Weight Loss Induced by Bariatric Surgery: A Potential Role for Leptin in Mediating Human Left Ventricular Hypertrophy J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4087 - 4093. [Abstract] [Full Text] [PDF]

				K. M. Minhas, S. A. Khan, S. V. Y. Raju, A. C. Phan, D. R. Gonzalez, M. W. Skaf, K. Lee, A. D. Tejani, A. P. Saliaris, L. A. Barouch, et al. Leptin repletion restores depressed {beta}-adrenergic contractility in ob/ob mice independently of cardiac hypertrophy J. Physiol., June 1, 2005; 565(2): 463 - 474. [Abstract] [Full Text] [PDF]

				F.-P. Xu, M.-S. Chen, Y.-Z. Wang, Q. Yi, S.-B. Lin, A. F. Chen, and J.-D. Luo Leptin Induces Hypertrophy via Endothelin-1-Reactive Oxygen Species Pathway in Cultured Neonatal Rat Cardiomyocytes Circulation, September 7, 2004; 110(10): 1269 - 1275. [Abstract] [Full Text] [PDF]

				K. Rahmouni and W. G. Haynes Leptin and the Cardiovascular System Recent Prog. Horm. Res., January 1, 2004; 59(1): 225 - 244. [Abstract] [Full Text]

				L. A. Barouch, D. E. Berkowitz, R. W. Harrison, C. P. O'Donnell, and J. M. Hare Disruption of Leptin Signaling Contributes to Cardiac Hypertrophy Independently of Body Weight in Mice Circulation, August 12, 2003; 108(6): 754 - 759. [Abstract] [Full Text] [PDF]

				J. Ren, K. K. Hintz, Z. K. F. Roughead, J. Duan, P. B. Colligan, B. H. Ren, K. J. Lee, and H. Zeng Impact of estrogen replacement on ventricular myocyte contractile function and protein kinase B/Akt activation Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1800 - H1807. [Abstract] [Full Text] [PDF]

				J. Ren, J. Duan, K. K Hintz, and B. H Ren High glucose induces cardiac insulin-like growth factor I resistance in ventricular myocytes: role of Akt and ERK activation Cardiovasc Res, March 1, 2003; 57(3): 738 - 748. [Abstract] [Full Text] [PDF]

				D. C.H Ng, N. W Court, C. G dos Remedios, and M. A Bogoyevitch Activation of signal transducer and activator of transcription (STAT) pathways in failing human hearts Cardiovasc Res, February 1, 2003; 57(2): 333 - 346. [Abstract] [Full Text] [PDF]

				B. J. Holycross and M. J. Radin Cytokines in Heart Failure: Potential Interactions with Angiotensin II and Leptin Mol. Interv., November 1, 2002; 2(7): 424 - 427. [Abstract] [Full Text]