atrial-natriuretic-factor and Autoimmune-Diseases

Circulating organ-specific autoantibodies are serological markers of destruction or impairment of the relevant endocrine tissue cells and may be associated with abnormal hormone levels with or without clinical evidence of overt disease. We sought organ-specific cardiac antibodies in patients with autoimmune polyendocrinopathy because of increasing evidence that the heart has endocrine characteristics (secretion of atrial natriuretic peptide [ANP] and other peptide hormones). Serum samples from 166 patients with polyendocrinopathy, 80 with autoimmunity confined to one gland, and 200 healthy blood donors were tested for these antibodies by means of immunofluorescence on human heart. Skeletal muscle was used to identify cross-reacting antibodies. Organ-specific cardiac antibodies were detected in significantly more of the patients with autoimmune polyendocrinopathy (28 [17%]) than of those with autoimmunity confined to one gland (1 [1%]) or of normal subjects (7 [3.5%]; p = 0.0001). Among the patients with autoimmune polyendocrinopathy, the prevalence of systemic hypertension was higher in those with cardiac autoantibodies than in those without (5/28 [18%] vs 2/80 [3%]; p = 0.01); the same was true for a family history of hypertension (11 [42%] vs 5 [7%]; p = 0.0001). There were no significant differences in mean basal or stimulated ANP concentrations between patients with or without antibodies or between patients and controls. 5 of the 22 antibody-positive patients had ANP concentrations outside the normal range, but these disturbances were not associated with systemic hypertension or a family history of the disorder. Patients with autoimmune polyendocrinopathy can have organ-specific cardiac antibodies, which may represent novel serological markers for an autoimmune form of systemic hypertension in the absence of overt cardiac disease.

Topics: Adult; Aged; Atrial Natriuretic Factor; Autoantibodies; Autoimmune Diseases; Biomarkers; Coronary Disease; Diabetes Mellitus, Type 1; Family Health; Female; Humans; Hypertension; Immunoglobulin G; Male; Middle Aged; Myocardium; Organ Specificity; Thyroid Diseases

The cardioprotective effects of carvedilol were studied in a rat model of experimental autoimmune myocarditis (EAM). After immunization, rats were orally administered 10 mg/kg/day carvedilol (group C, n = 15) or a vehicle control (Group V, n = 12) for 3 weeks. On day 21, echocardiography and haemodynamic parameters, myocarditis areas, and cytokine concentrations were measured. Serum carvedilol concentrations ranged from 10.5 +/- 2.6 to 31.7 +/- 9.3 ng/ml over a 24 h period on day 20. Carvedilol decreased the myocarditis areas (23.07 +/- 1.6 versus 33.65 +/- 2.71%, P < 0.0001). The left ventricular fractional shortening and the absolute value of +dP/dt or -dP/dt were significantly higher in Group C. Heart rate, systolic blood pressure, left ventricular end-diastolic pressure and central venous pressure were significantly lower in Group C. The serum and mRNA levels of interleukin (IL)-1beta (53.58 +/- 6.42 versus 98.75 +/- 6.53 pg/ml, P < 0.0001 and 0.298 +/- 0.04 versus 0.818 +/- 0.252, P < 0.0001, respectively) and TNF-alpha (14.82 +/- 1.95 versus 29.52 +/- 3.7 pg/ml, P = 0.0008 and 0.088 +/- 0.006 versus 0.168 +/- 0.072, P = 0.0051, respectively) were markedly decreased, whereas IL-10 (24.92 +/- 2.94 versus 15.25 +/- 3.13 pg/ml, P = 0.015 and 0.302 +/- 0.022 versus 0.107 +/- 0.02, P < 0.0001, respectively) and IL-1 receptor antagonist (1.95 +/- 0.28 versus 0.52 +/- 0.10 pg/ml, P < 0.0001 and 0.112 +/- 0.009 versus 0.051 +/- 0.002, P < 0.0001, respectively) were markedly increased in the Group C. These results indicate that in rats carvedilol protects against EAM.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Carbazoles; Carvedilol; Cytokines; Enzyme-Linked Immunosorbent Assay; Male; Myocarditis; Organ Size; Propanolamines; Rats; Rats, Inbred Lew; Receptors, Adrenergic, beta-2; RNA, Messenger

The effect of carperitide, recombinant human atrial natriuretic peptide, on chronic heart failure (HF) has not been clarified. We investigated the beneficial effects of chronic carperitide treatment in rats with HF after experimental autoimmune myocarditis. A 28-day infusion of carperitide (n = 14) or vehicle (n = 14) was administrated to the rats 4 weeks after experimental autoimmune myocarditis induction. After 4 weeks, the myocardial levels of cyclic guanosine monophosphate (cGMP), left ventricular function, myocyte hypertrophy, interstitial fibrosis, myocardial capillary vessel density, and activity of one prominent substrate of cGMP, vasodilator-stimulated phosphoprotein (VASP) that may enhance angiogenesis, were measured. Carperitide treatment increased the myocardial levels of cGMP and attenuated the functional severity along with a decreased myocyte cross-sectional area, interstitial fibrosis, and an increased capillary to myocyte ratio. Furthermore, carperitide treatment enhanced the phosphorylation of VASP at Ser239, which was preferentially phosphorylated by cGMP-dependent protein kinase but not Ser157, which was preferentially phosphorylated by cyclic adenosine monophosphate-dependent protein kinase. Long-term carperitide treatment attenuates ventricular remodeling and ameliorates the progression of chronic HF. The effects of carperitide treatment are associated with increased neovascularization among the residual myocytes and an increase of VASP activation.

Topics: Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Capillaries; Cell Adhesion Molecules; Cell Size; Coronary Vessels; Cyclic GMP; Fibrosis; Heart Failure; Male; Microfilament Proteins; Myocarditis; Myocardium; Neovascularization, Physiologic; Phosphoproteins; Phosphorylation; Random Allocation; Rats; Rats, Inbred Lew; Recombinant Proteins; Stroke Volume; Ventricular Function, Left; Ventricular Remodeling

Chymase has been known as a local angiotensin II-generating enzyme in the cardiovascular system in dogs, monkeys, hamsters, and humans; however, recently it was reported that chymase also has various other functions. Therefore, we decided to examine whether the inhibition of chymase improves disease conditions associated with the pathophysiology of dilated cardiomyopathy in rats and its possible mechanism of action as rat chymase is unable to produce angiotensin II. We examined the effect of TY-51469, a novel chymase inhibitor (0.1 mg/kg/day [group CYI-0.1, n = 15] and 1 mg/kg/day [group CYI-1, n = 15]), in myosin-immunized postmyocarditis rats. Another group of myosin-immunized rats was treated with vehicle (group V, n = 15). Age-matched normal rats without immunization (group N, n = 10) were also included in the study. After 4 weeks of treatment, we evaluated cardiac function; area of fibrosis; fibrogenesis; levels of transforming growth factor (TGF)-beta1 and collagen III; hypertrophy and its marker, atrial natriuretic peptide (ANP); and mast cell activity. Survival rate and myocardial functions improved dose-dependently with chymase inhibitor treatment after myosin immunization. A reduction in the percent area of myocardial fibrosis, fibrogenesis, myocardial hypertrophy, and mast cell activity along with a reduction in TGF-beta1, collagen III, and ANP levels in the myocardium were noted in postmyocarditis rats that received chymase inhibitor treatment. The treatment also decreased myocardial aldosterone synthase levels in those animals. Inhibition of chymase reduces the pathogenesis of postmyocarditis dilated cardiomyopathy and progression to heart failure by preventing the pathological remodeling and residual inflammation in rats.

Topics: Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Cardiomyopathy, Dilated; Chymases; Collagen Type III; Cyclin D1; Disease Progression; Enzyme Inhibitors; Heart Failure; Histamine; Humans; Macaca mulatta; Male; Myocarditis; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Sulfonamides; Survival Rate; Thiophenes; Transforming Growth Factor beta1

Rat experimental autoimmune myocarditis (EAM) is a T cell-mediated disease that resembled the giant cell myocarditis seen in humans. Soluble CTLA4 improves some autoimmune diseases by blocking costimulatory signals on T cell. We investigated the effect of hydrodynamics-based naked plasmid DNA encoding CTLA4-immunoglobulin (Ig) gene delivery.. Lewis rats were immunized with cardiac myosin and treated with hydrodynamic-based transfection, namely a rapid tail vein injection of a large volume of pCAGGS encoding CTLA4-Ig chimera solution on Day 0. The vector-derived CTLA4-Ig mRNA expressions were mainly detected in the liver and plasma CTLA4-Ig protein levels were maintained at about 2 mug/mL during the experiment period. On Day 17, the ratio of heart to body weight, the amount of mRNA of atrial natriuretic peptide, and the inflammatory areas in CTLA4 group were significantly lower than in the control group treated with empty plasmid. Maximum rate of intraventricular pressure rise and decline (dP/dT), minimum dP/dT, left ventricular end-diastolic pressure, and central venous pressure improved significantly after treatment with CTLA4-Ig. On Day 14, expressions of IL-2 in popliteal lymph nodes in the CTLA4-Ig group were significantly lower than in the control group.. Hydrodynamics-based transfection of plasmid encoding CTLA4-Ig chimera dramatically prevented EAM.

Topics: Abatacept; Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Disease Models, Animal; Genetic Therapy; Immunoconjugates; Interleukin-2; Lymph Nodes; Male; Myocarditis; Plasmids; Popliteal Artery; Rats; Rats, Inbred Lew; RNA, Messenger; Time Factors; Transfection; Ventricular Pressure

Although myocarditis has been implicated in the pathogenesis of heart failure, a definitive relationship between myocardial inflammation, cardiac dysfunction, and changes in myocyte gene expression has not been established. In this study, we examined the hypothesis that myocardial inflammation and replacement fibrosis following an autoimmune response can progress to cardiac dysfunction and may result in progression to the heart failure phenotype. SWXJ mice were immunized with cardiac myosin on day 0 and day 7, in order to induce an autoimmune response to the myosin protein. Cardiac catheterization via the right carotid artery was performed on days 14, 21, 28, 35, and 42, using a 1.4F Millar transducer-tipped catheter. Hearts were weighed, and cross-sections were cut and stained with either haematoxylin and eosin or Masson's trichrome, in order to identify areas of inflammation and/or fibrosis. Myocardial gene expression was determined by Northern blot analysis. In mice with histological evidence of myocarditis, the heart weight/body weight ratio increased beginning on day 14, and cardiac function decreased beginning on day 21. Myocardial inflammation was accompanied by significant fibrosis beginning on day 21. Quantitation of mRNA showed expression of ventricular atrial naturietic factor, as well as a decrease in myosin heavy chain alpha, beginning on day 21. These data demonstrate that autoimmune inflammation of the heart results in significant cardiac dysfunction, leading to phenotypic alterations similar to those demonstrated in human heart failure and animal models of heart failure.

Topics: Animals; Atrial Natriuretic Factor; Autoantigens; Autoimmune Diseases; Body Weight; Endomyocardial Fibrosis; Gene Expression Regulation; Heart; Heart Failure; Male; Mice; Mice, Inbred Strains; Models, Animal; Molecular Motor Proteins; Muscle Proteins; Myocarditis; Myocardium; Myosin Heavy Chains; Myosins; Organ Size; RNA, Messenger; T-Lymphocytes, Cytotoxic; Ventricular Dysfunction, Left

Effects of nitric oxide (NO) synthase inhibition on blood pressure and on the course of Heymann nephritis was examined in rats. L-NG-nitroarginine-methylester (L-NAME, 10 mg/100 ml in the drinking water for 12 weeks) was used as an inhibitor of NO synthase. Urinary excretion of guanosine 3',5'-cyclic monophosphate (cGMP), a second messenger of NO, was used as an indirect estimate of NO activity. Rats were divided into the following groups: control, nephritis, L-NAME, and nephritis-L-NAME. Urinary cGMP excretion was lower in the nephritis group (p < 0.05) and in the nephritis-L-NAME group (p < 0.005) compared with controls. Plasma atrial natriuretic peptide (ANP) levels were elevated in the nephritis (p < 0.001) and in the nephritis-L-NAME groups (p < 0.05. L-NAME treatment alone did not have any effect on plasma ANP levels. Blood pressure rose progressively in all L-NAME-treated rats. Most marked albuminuria developed in the nephritis-L-NAME group. No differences in the immunohistological findings were observed between the nephritis and the nephritis-L-NAME groups. NO synthase inhibition causes hypertension and aggravates albuminuria in chronic nephritis. Moreover, nephritis itself may decrease then production of cGMP either as a consequence of blunted NO activity or, in addition, because of ANP resistance. It appears that NO synthase inhibition does not change the immunological course of Heymann nephritis but rather the increased hemodynamic load makes the course of nephritis worse.

Topics: Albuminuria; Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Blood Pressure; Complement C3; Cyclic GMP; Enzyme Inhibitors; Female; Glomerulonephritis; Immunoglobulin G; Immunohistochemistry; Kidney Glomerulus; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Renin; Time Factors

Pharmacological strategies have been employed to manipulate the response to atriopeptin (AP-28; ANF 99-126) in rats. These approaches include: heparin infusion which blocks the natriuresis-diuresis produced by exogenous AP infusion or by acute volume expansion; and autoimmune rats with endogenous antibody that blocks the natriuresis-diuresis produced by administration of exogenous AP or by acute volume expansion in anesthetized rats. Administration of the pressor analog 1-deamino-arg8-vasopressin (dAVP) to rats produces an elevation in systemic and right atrial blood pressure and markedly increases atriopeptin blood levels. The dAVP also produces a delayed natriuresis-diuresis which is effectively blunted in the autoimmune or heparin treated rats. The above approaches provide tools, in the absence of a specific receptor antagonist, with which to validate the intrinsic involvement of AP in physiological, pharmacological, or pathophysiological events.

Topics: Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Blood Volume; Diuresis; Heparin; Natriuresis; Rats; Vasopressins