ag-490 and Ventricular-Dysfunction--Left

Acute heart failure (AHF) is a burden disease, with high mortality and re-hospitalisations. Using an ex-vivo model of AHF, we have previously reported that sphingosine-1-phosphate (S1P) confers cardioprotection. However, the mechanisms remain to be elucidated. In the present study, we aimed to examine the role of the cardioprotective signal transducer and activator of transcription 3 (STAT3) in S1P mediated improved functional recovery in AHF.. Isolated hearts from male Long-Evans rats were subjected to hypotensive AHF for 35 min followed by a recovery phase of 30 min (n ≥ 4/group). S1P (10 nM) was given during either the hypotensive or the recovery phase with/without an inhibitor of STAT3, AG490. Functional parameters were recorded throughout the experiment.. Following an AHF insult, S1P, given during the recovery phase, improved the heart rate (HR) compared to the control (175.2 ± 30.7 vs. 71.6 ± 27.4 beats per minute (BPM); p < 0.05), with no changes in the left ventricular developed pressure. This effect was associated with an increase in phosphorylated STAT3 levels in the nucleus. Addition of AG490 with S1P abolished the cardioprotective effect of S1P (42.3 ± 17.1 vs. 148.8 ± 26.4 BPM for S1P; p < 0.05).. Our data suggest that S1P protects in an ex-vivo rat heart model of AHF by activation of STAT3 and provide further evidence for the usage of S1P as a potential therapy in patients suffering from AHF.

Topics: Acute Disease; Animals; Blood Pressure; Cardiotonic Agents; Heart Failure; Heart Rate; In Vitro Techniques; Lysophospholipids; Male; Phosphorylation; Rats; Rats, Long-Evans; Sphingosine; STAT3 Transcription Factor; Tyrphostins; Ventricular Dysfunction, Left

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 Ca(2+) 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/TR(90), +/-dL/dt), and fura-fluorescence intensity change (DeltaFFI). NO and nitric oxide synthase (NOS) activity were assessed by the Griess and the (3)H-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 DeltaFFI in WKY, but not in SHR myocytes. Leptin did not affect TPS, TR(90), or +/- dL/dt. The difference in leptin-induced contractile response between the WKY and the SHR groups was abolished by the NOS inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), but not by elevated extracellular Ca(2+). 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.

Topics: Animals; Blood Pressure; Calcium; Carrier Proteins; Cell Size; DNA-Binding Proteins; Enzyme Inhibitors; Heart Ventricles; Hypertension; Imidazoles; Janus Kinase 2; Leptin; Mitogen-Activated Protein Kinase Kinases; Myocardial Contraction; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Cell Surface; Receptors, Leptin; Signal Transduction; STAT3 Transcription Factor; Trans-Activators; Tyrphostins; Ventricular Dysfunction, Left