leptin and Ventricular-Dysfunction--Left

Obese subjects have elevated leptin levels, which have been associated with increased risk of cardiovascular events. Because leptin has direct cellular effects on various tissues, we tested the hypothesis that leptin levels are associated with cardiac structure or function in patients with coronary artery disease (CAD).. The study population consisted of 1 601 CAD patients, of whom 42% had type 2 diabetes mellitus. Plasma leptin was measured in fasted state and an echocardiography performed. Leptin levels were not related to LV dimensions or LV ejection fraction (NS for all), but higher leptin levels were associated with elevated E/E' (9.43 vs. 11.94 in the lowest and the highest leptin quartile, respectively; p=0.018 for trend). Correspondingly, a decreasing trend was observed in E/A (1.15 vs. 1.06; p=0.037). These associations were independent of obesity and other relevant confounding variables.. We conclude that elevated plasma leptin levels are associated with impaired left ventricular diastolic function in patients with CAD independently of obesity and other confounding variables. Leptin may be one of the mechanistic links explaining the development of congestive heart failure in obese subjects.

Topics: Aged; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diastole; Echocardiography; Female; Heart Failure; Humans; Leptin; Male; Middle Aged; Obesity; Risk Factors; Ventricular Dysfunction, Left

Results from animal experimentation suggest a 2-way interaction between leptin and the sympathetic nervous system, with leptin causing sympathetic activation and conversely, with the sympathetic system exercising regulatory feedback inhibition over leptin release. We have now tested this hypothesis in humans. In the absence of results from leptin infusions, to test for sympathetic stimulation of leptin release, we sought a quantitative naturalistic linkage of sympathetic activity with leptin plasma concentration across a broad range of leptin values in men of widely differing adiposity. Renal norepinephrine spillover was correlated with plasma leptin (r=0.628, P<0.01), but other measures of sympathoadrenal function did not. To test for sympathetic and adrenomedullary inhibition of leptin release, we studied clinical models of high sympathetic tone, heart failure, and essential hypertension, in which lowered plasma leptin levels might have been expected but were not found; a model of low sympathetic activity, pure autonomic failure, in which plasma leptin level was normal (6.1+/-1.2 vs 12.8+/-3.1 ng/mL in healthy subjects); and a clinical model of reduced epinephrine secretion, healthy aging, in which plasma leptin level again was normal (5.7+/-1.1 ng/mL vs 4.0+/-0.9 ng/mL in men >60 years and <35 years, respectively). Paradoxically, leptin concentration was elevated in heart failure, caused entirely by reduced renal clearance of leptin release, 142.0+/-30.5 mL/min, compared with 56.9+/-18.9 mL/min (P<0.05). These results provide some support for the view that leptin stimulates the sympathetic nervous system, at least for renal sympathetic outflow, but do not confirm the concept of regulatory feedback inhibition of leptin release by the sympathetic nervous system.

Topics: Adult; Aging; Antihypertensive Agents; Autonomic Nervous System Diseases; Clonidine; Epinephrine; Female; Humans; Hypertension; Infusions, Intravenous; Leptin; Male; Middle Aged; Nitroprusside; Norepinephrine; Obesity; Sympathetic Nervous System; Ventricular Dysfunction, Left

Background Marfan syndrome (MFS) is a genetically transmitted connective tissue disorder characterized by aortic root dilatation, dissection, and rupture. Molecularly, MFS pathological features have been shown to be driven by increased angiotensin II in the aortic wall. Using an angiotensin II-driven aneurysm mouse model, we have recently demonstrated that local inhibition of leptin activity restricts aneurysm formation in the ascending and abdominal aorta. As we observed de novo leptin synthesis in the ascending aortic aneurysm wall of patients with MFS, we hypothesized that local counteracting of leptin activity in MFS may also prevent aortic cardiovascular complications in this context. Methods and Results

Topics: Animals; Aorta; Aortic Aneurysm; Dilatation, Pathologic; Disease Models, Animal; Fibrillin-1; Hormone Antagonists; Leptin; Male; Marfan Syndrome; Mice, Mutant Strains; Signal Transduction; Systole; Vascular Remodeling; Ventricular Dysfunction, Left; Ventricular Function, Left

Acute MI induces leptin expression in the heart, however the role of myocardial leptin in cardiac ischemia and reperfusion (IR) remains unknown. To shed light on the effects of elevated levels of leptin in the myocardium, we overexpressed cardiac leptin and assessed local remodeling and myocardial function in this context.. Cardiac leptin overexpression was stimulated in mice undergoing IR by a single intraperitoneal injection of leptin antagonist (LepA). All mice exhibited a normal pattern of body weight gain. A rapid, long-term upregulation of leptin mRNA was demonstrated in the heart, adipose, and liver tissues in IR/LepA-treated mice. Overexpressed cardiac leptin mRNA extended beyond postoperative day (POD) 30. Plasma leptin peaked 7.5 hours postoperatively, especially in IR/LepA-treated mice, subsiding to normal levels by 24 hours. On POD-30 IR/LepA-treated mice demonstrated cardiomyocyte hypertrophy and perivascular fibrosis compared to IR/saline controls. Echocardiography on POD-30 demonstrated eccentric hypertrophy and systolic dysfunction in IR/LepA. We recorded reductions in Ejection Fraction (p<0.001), Fraction Shortening (p<0.01), and Endocardial Fraction Area Change (p<0.01), and an increase in Endocardial Area Change (p<0.01). Myocardial remodeling in the context of IR and cardiac leptin overexpression was associated with increased cardiac TGFβ ligand expression, activated Smad2, and downregulation of STAT3 activity.. Cardiac IR coinciding with increased myocardial leptin synthesis promotes cardiomyocyte hypertrophy and fibrosis and potentiates myocardial dysfunction. Plasma leptin levels do not reflect cardiac leptin synthesis, and may not predict leptin-related cardiovascular morbidity. Targeting cardiac leptin is a potential treatment for cardiac IR damage.

Topics: Animals; Disease Models, Animal; Echocardiography; Leptin; Male; Mice; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Smad2 Protein; STAT3 Transcription Factor; Ventricular Dysfunction, Left; Ventricular Remodeling

Chagas disease (CD) induces autonomic dysfunction and inflammatory activity, which may promote metabolic abnormalities. We studied metabolism and his correlation with Autonomic Nervous System (ANS) and inflammation in CD.. Sixty subjects were divided into 4 groups: control group (CG), IF (indeterminate form) group; ECG group (ECG abnormalities and normal left ventricular systolic function), and LVD group (left ventricular sistolic dysfunction). Levels of adiponectin, leptin, insulin, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were assayed in serum samples by ELISA. ANS was assessed by heart rate variability in frequency domain in 24-hour Holter and postural tilt test (rest and orthostatic position). High frequency (HFr) component values were used to estimate parasympathetic activity and low frequency (LFr) component, sympathetic activity. Analyzes were made of the correlations of each of the metabolic parameters (leptin and adiponectin) with the inflammatory cytokines (interleukin-6 and TNF- alpha) and with the ANS assessment measurements. No significant differences were observed in leptin and insulin levels. Adiponectin was higher in ECG and LVD groups: [CG = 4766.5 (5529.5), IF = 4003.5 (2482.5), ECG = 8376.5 (8388.5), LVD = 8798 (4188.0) ng/mL, p<0.001)]. IL-6 and TNF-alpha were higher in LVD group: [IL-6: CG = 1.85 (6.41); IF = 1.58 (1.91); ECG = 1.0 (1.57); LVD= 31.44 (72.19) pg/ml; p = 0.001. TNF-alpha: CG = 22.57 (88.2); IF = 19.31 (33.16); ECG = 12.45 (3.07); LVD = 75.15 (278.57) pg/ml; p = 0.04]. Adiponectin levels had a positive association with the HFr component (r = 0.539; p = 0.038) and an inverse association with the LFr component (r = - 0.539; p = 0.038) in ECG group. Leptin levels had a negative association with the HFr component (r= - 0.632; p = 0.011) and a positive association with the LFr component (r = 0.632; p = 0.011) in LVD group.. We found increased adiponectin levels in Chagas' heart disease with systolic dysfunction and in patients with ECG abnormalities and normal systolic function at rest. Adipocytokines levels (adiponectin and leptin) were associated with ANS parameters in Chagas' heart disease.

Topics: Adipokines; Adiponectin; Adult; Autonomic Nervous System; Chagas Cardiomyopathy; Electrocardiography; Female; Heart; Heart Rate; Humans; Inflammation; Insulin; Interleukin-6; Leptin; Male; Middle Aged; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left

Increasing adiposity increases the risk for left ventricular (LV) hypertrophy. Adipokines are hormone-like substances from adipose tissue that influence several metabolic pathways relevant to LV hypertrophy. Data were obtained from participants enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA) who underwent magnetic resonance imaging of the heart and who also had fasting venous blood assayed for 4 distinct adipokines (adiponectin, leptin, tumor necrosis factor-α, and resistin). One-thousand four hundred sixty four MESA participants had complete data. The mean age was 61.5 years, the mean body mass index was 27.6 kg/m², and 49% were women. With adjustment for age, gender, race, height, and weight, multivariate linear regression modeling revealed that a 1-SD increment in leptin was significantly associated with smaller LV mass (ß: -4.66% predicted, p <0.01), LV volume (-5.87% predicted, p <0.01), stroke volume (-3.23 ml, p <0.01), and cardiac output (-120 ml/min, p = 0.01) as well as a lower odds ratio for the presence of LV hypertrophy (odds ratio 0.65, p <0.01), but a higher ejection fraction (0.44%, p = 0.05). Additional adjustment for the traditional cardiovascular disease risk factors, insulin resistance, physical activity, education, income, inflammatory biomarkers, other selected adipokines, and pericardial fat did not materially change the magnitude or significance of the associations. The associations between the other adipokines and LV structure and function were inconsistent and largely nonsignificant. In conclusion, the results indicate that higher levels of leptin are associated with more favorable values of several measures of LV structure and function.

Topics: Adiponectin; Aged; Cardiac Output; Female; Humans; Hypertrophy, Left Ventricular; Leptin; Linear Models; Magnetic Resonance Imaging, Cine; Male; Middle Aged; Resistin; Risk Factors; Stroke Volume; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left; Ventricular Function, Left

The expression of leptin and resistin is known to be positively correlated with the incidence of chronic heart failure (CHF). Both adipokines have been implicated in immunomodulation and cardiac remodelling. Therefore, we performed for the first time a clinical study to elucidate the effects of leptin and resistin on progression of CHF in patients with non-ischaemic dilated (DCM) and inflammatory (DCMi) cardiomyopathy.. For the clinical study 120 patients were divided into a control (n = 16), DCM (n = 52), and DCMi (n = 52) group to determine the effect of leptin and resistin on CHF progression. Nuclear factor-κB (NF-κB) activation, reactive oxygen species generation, and tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) expression following adipokine exposition were determined in vitro in cardiomyocytes. Leptin and resistin systemic plasma levels and not cardiac expression were significantly elevated in patients with DCM (leptin, 13.12 ± 17.2 ng/mL, P < 0.05; resistin, 6.87 ± 2.25 ng/mL, P < 0.05) and DCMi (leptin, 13.63 ± 16 ng/mL, P < 0.05; resistin, 7.27 ± 2.2 ng/mL, P < 0.05) compared with the control group (leptin, 7.34 ± 5.7 ng/mL; resistin, 4.4 ± 1.18 ng/mL). A multivariate linear regression model revealed low leptin and resistin plasma levels as contributors for favourable cardiac functional parameters at 6-month follow-up independent of inflammatory conditions. Cell culture experiments in vitro showed leptin and resistin to be potent regulators of TNF-α and IL-6 expression in cardiomyocytes, leading to significantly increased redox stress in cardiac cells.. High leptin and resistin expression in patients with DCM and DCMi is associated with CHF progression, i.e. severe cardiac dysfunction, independent of immune responses.

Topics: Adult; Biomarkers; Cardiomyopathies; Disease Progression; Female; Health Status Indicators; Heart Failure; Hemodynamics; Humans; Inflammation; Leptin; Male; Middle Aged; Multivariate Analysis; Prognosis; Resistin; ROC Curve; Statistics as Topic; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left

Leptin is known to exert cardiodepressive effects and to induce left ventricular (LV) remodelling. Nevertheless, the autocrine and/or paracrine activities of this adipokine in the context of post-infarct dysfunction and remodelling have not yet been elucidated. Therefore, we have investigated the evolution of myocardial leptin expression following myocardial infarction (MI) and evaluated the consequences of specific cardiac leptin inhibition on subsequent LV dysfunction. Anaesthetized rats were subjected to temporary coronary occlusion. An antisense oligodesoxynucleotide (AS ODN) directed against leptin mRNA was injected intramyocardially along the border of the infarct 5 days after surgery. Cardiac morphometry and function were monitored by echocardiography over 11 weeks following MI. Production of myocardial leptin and pro-inflammatory cytokines interleukin (IL)-1β and IL-6 were assessed by ELISA. Our results show that (1) cardiac leptin level peaks 7 days after reperfused MI; (2) intramyocardial injection of leptin-AS ODN reduces early IL-1β and IL-6 overexpression and markedly protects contractile function. In conclusion, our findings demonstrate that cardiac leptin expression after MI could contribute to the evolution towards heart failure through autocrine and/or paracrine actions. The detrimental effect of leptin could be mediated by pro-inflammatory cytokines such as IL-1β and IL-6. Our data could constitute the basis of new therapeutic approaches aimed to improve post-MI outcome.

Topics: Animals; DNA, Antisense; Echocardiography; Enzyme-Linked Immunosorbent Assay; Heart; Interleukin-1beta; Interleukin-6; Leptin; Male; Myocardial Infarction; Myocardium; Rats; Rats, Wistar; Time Factors; Ventricular Dysfunction, Left

There is an increasing interest in the role of leptin in cardiovascular pathophysiology, including proinflammatory effects. Many studies have reported elevated leptin levels in non-cachectic patients with chronic heart failure (CHF), however, the role of leptin in CHF remains unclear.. To assess the relationship between leptin levels in patients with CHF and left ventricular (LV) systolic dysfunction in relation to ventilatory response to exercise and hsCRP levels.. The study group consisted of 41 patients (mean age 50.2 ± 9.3 years) with stable CHF and LV ejection fraction < 45% and eight healthy controls (mean age 43.6 ± 14.7 years). Sixteen (39%) patients had coronary artery disease. All subjects underwent anthropometric measurements (weight, height, and waist circumference), standard echocardiography, and maximal cardiopulmonary exercise treadmill test. Biochemical analysis included the assessment of leptin and hsCRP levels as well as white blood count (WBC) and erythrocyte sedimention rate.. Leptin levels, including body mass index (BMI)-adjusted leptin levels, were significantly higher in the CHF patients than in the controls (9.2 ± 7.5 vs 2.9 ± 1.25 ng/mL; p = 0.005). We found significantly higher WBC, neutrophil count, lymphocyte percentage and BNP levels in the CHF group vs controls. There were significant correlations in the CHF group between leptin levels and BMI (r = 0.55; p < 0.05), waist circumference (r = 0.49; p < 0.05), leukocyte count (r = 0.41; p < 0.05), hsCRP levels (r = 0.34; p < 0.05), and peak VO₂ (r = -0.34; p < 0.05). Multivariate step forward regression analysis showed that peak VO₂ was significantly related with leptin levels. After adding VE/VCO₂ slope to the multivariate regression analysis model, only VE/VCO₂ slope was independently associated with leptin levels.. There is a significant relationship between serum leptin levels and peak VO₂, VE/VCO₂ slope and levels of inflammatory markers in patients with CHF.

Topics: Adult; Biomarkers; Body Mass Index; C-Reactive Protein; Case-Control Studies; Female; Heart Failure; Humans; Inflammation; Leptin; Male; Middle Aged; Ventricular Dysfunction, Left

The 16 kDa adipokine leptin has been shown to exert direct hypertrophic effects on cultured cardiomyocytes although its role as an endogenous contributor to postinfarction remodeling and heart failure has not been determined. We therefore investigated the effect of leptin receptor blockade in vivo on hemodynamic function and cardiac hypertrophy following coronary artery ligation (CAL). Cardiac function and biochemical parameters were measured in rats subjected to 7 or 28 days of left main CAL in the presence and absence of a leptin receptor antibody. Animals subjected to an identical treatment in which the artery was not tied served as sham-operated controls. CAL produced myocardial hypertrophy, which was most pronounced 28 days postinfarction as demonstrated by increases in both left ventricular weight-to-body weight ratio and atrial natriuretic peptide gene expression, both of which were abrogated by leptin receptor antagonism. Leptin receptor blockade also significantly improved left ventricular systolic function, attenuated the increased left ventricular end-diastolic pressure, and reduced the expression of genes associated with extracellular matrix remodeling 28 days following CAL. In conclusion, the ability of a leptin receptor-neutralizing antibody to improve cardiac function offers evidence that endogenous leptin contributes to cardiac hypertrophy following CAL. The possibility exists that targeting the myocardial leptin receptor represents a viable and novel approach toward attenuating postinfarction remodeling.

Topics: Animals; Antibodies; Disease Models, Animal; Extracellular Matrix; Hemodynamics; Hypertrophy, Left Ventricular; Leptin; Male; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Time Factors; Ventricular Dysfunction, Left; Ventricular Pressure; Ventricular Remodeling

It is not known how carbohydrate and fat intake affect the development of left ventricular (LV) hypertrophy and contractile dysfunction in response to pressure overload. We hypothesized that a low-carbohydrate/high-fat diet prevents LV hypertrophy and dysfunction compared with high-carbohydrate diets.. Rats were fed high-carbohydrate diets composed of either starch or sucrose, or a low-carbohydrate/high-fat diet, and underwent abdominal aortic banding (AAB) for 2 months. AAB increased LV mass with all diets. LV end-diastolic and systolic volumes and the ratio of the mRNA for myosin heavy chain beta/alpha were increased with both high-carbohydrate diets but not with the low-carbohydrate/high-fat diet. Circulating levels of insulin and leptin, both stimulants for cardiac growth, were lower, and free fatty acids were higher with the low-carbohydrate/high-fat diet compared with high-carbohydrate diets. Among animals that underwent AAB, LV volumes were positively correlated with insulin and LV mass correlated with leptin.. A low-carbohydrate/high-fat diet attenuated pressure overload-induced LV remodeling compared with high-carbohydrate diets. This effect corresponded to lower insulin and leptin concentrations, suggesting they may contribute to the development of LV hypertrophy and dysfunction under conditions of pressure overload.

Topics: Animals; Blood Pressure; Diet, Carbohydrate-Restricted; Dietary Carbohydrates; Dietary Fats; Disease Models, Animal; Hypertension; Hypertrophy, Left Ventricular; Insulin; Leptin; Male; Nutritional Status; Rats; Rats, Wistar; Risk Factors; Ultrasonography; Ventricular Dysfunction, Left

Controversy exists regarding the effects of statin therapy on progressive insulin resistance (IR) and its consequences, in the present study a rat model of spontaneously developing type II diabetes mellitus (DM) was used to examine the impact of atorvastatin (AS) vs pravastatin (PS).. The Otsuka Long-Evans Tokushima Fatty rats were either untreated or treated with 100 mg/kg per day of AS or PS from 6 weeks of age for 24 weeks. AS achieved much greater lipid lowering than PS. Serial oral glucose tolerance tests revealed new-onset diabetes was delayed by PS only. The untreated rats exhibited a progressive decrease in plasma adiponectin, increases in plasma leptin and tumor necrosis factor-alpha, and reduction of plasma nitric oxide (NO), which were limited more by PS than AS. PS, but not AS, enhanced adiponectin mRNA expression in white adipose tissue at 30 weeks. Cardiac endothelial NO synthase expression was upregulated, and overexpression of both transforming growth factor-beta1 and monocyte chemoattractant protein-1 mRNA was limited more by PS than AS. Coronary perivascular fibrosis at 30 weeks was suppressed only by PS, which was accompanied by preserved left ventricular diastolic function assessed with Doppler echocardiography.. The moderate lipid lowering by PS, but not the intensive lipid lowering by AS, prevented new-onset DM and diastolic dysfunction in a rat model of IR, and this was associated with preferable adipocytokine profiles and cardiac redox states.

Topics: Adiponectin; Adipose Tissue; Animals; Anticholesteremic Agents; Atorvastatin; Chemokine CCL2; Diabetes Mellitus, Type 2; Disease Models, Animal; Gene Expression Regulation; Glucose; Heptanoic Acids; Hypertriglyceridemia; Insulin Resistance; Leptin; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type III; Pravastatin; Pyrroles; Rats; Rats, Long-Evans; Rats, Mutant Strains; RNA, Messenger; Transforming Growth Factor beta1; Ventricular Dysfunction, Left

Leptin is produced primarily by adipocytes. Although originally associated with the central regulation of satiety and energy metabolism, increasing evidence indicates that leptin may be an important mediator in cardiovascular pathophysiology. The aim of the present study was to investigate plasma leptin levels in patient with Chagas' heart disease and their relation to different forms of the disease. We studied 52 chagasic patients and 30 controls matched for age and body mass index. All subjects underwent anthropometric, leptin and N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements and were evaluated by echocardiography, 12-lead electrocardiogram (ECG), and chest X-ray. All patients had fasting blood samples taken between 8:00 and 9:00 am. Chagasic patients were divided into 3 groups: group I (indeterminate form, IF group) consisted of 24 subjects with 2 positive serologic reactions for Chagas' disease and no cardiac involvement as evaluated by chest X-rays, ECG and two-dimensional echocardiography; group II (showing ECG abnormalities and normal left ventricular systolic function, ECG group) consisted of 14 patients; group III consisted of 14 patients with congestive heart failure (CHF group) and left ventricular dysfunction. Serum leptin levels were significantly lower (P < 0.001) in the CHF group (1.4 +/- 0.8 ng/mL) when compared to the IF group (5.3 +/- 5.3 ng/mL), ECG group (9.7 +/- 10.7 ng/mL), and control group (8.1 +/- 7.8 ng/mL). NT-proBNP levels were significantly higher (P < 0.001) in the CHF group (831.8 +/- 800.1 pg/mL) when compared to the IF group (53.2 +/- 33.3 pg/mL), ECG group (83.3 +/- 57.4 pg/mL), and control group (32 +/- 22.7 pg/mL). Patients with Chagas' disease and an advanced stage of CHF have high levels of NT-ProBNP andlow plasma levels of leptin. One or more leptin-suppressing mechanisms may operate in chagasic patients.

Topics: Adult; Biomarkers; Body Mass Index; Case-Control Studies; Chagas Cardiomyopathy; Chagas Disease; Echocardiography; Electrocardiography; Female; Fluoroimmunoassay; Heart Failure; Humans; Leptin; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Ventricular Dysfunction, Left

Neuropeptide Y (NPY) is released during sympathetic stimulation and mediates the central effects of the adipostatic hormone leptin. The plasma concentration of NPY and leptin is increased in patients with end stage renal disease (ESRD), but it is unknown whether these substances are related to biochemical markers of sympathetic activity and to alterations in left ventricular (LV) mass and function in these patients.. We investigated the relationship between NPY, norepinephrine (NE), leptin and echocardiographic measurements in a cross-sectional study in 198 patients with ESRD.. NPY was directly related to plasma NE and heart rate but it was largely independent of arterial pressure and of retention of metabolic waste products. NPY was significantly higher in patients with LV hypertrophy and in those with LV systolic dysfunction than in those without these alterations. Of note, NPY emerged as an independent correlate of LV mass index and of LV ejection fraction (LVEF) (both P

Topics: Adult; Aged; Biomarkers; Cohort Studies; Cross-Sectional Studies; Echocardiography; Female; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Myocardium; Neuropeptide Y; Norepinephrine; Risk Factors; 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