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

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


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 (ΔFFI). 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 ΔFFI 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, Nω-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.

Original languageEnglish (US)
Pages (from-to)69-74
Number of pages6
Issue number1
StatePublished - 2002
Externally publishedYes


  • Cardiac function
  • Hypertension, obesity
  • Kinase
  • Myocytes
  • Nitric oxide
  • Signal transduction


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