natriuretic-peptide--c-type and Inflammation

The up-to-day world-wide data about the structure, distribution, and physiological effects of the most poorly known among the natriuretic peptides--the C-type (CNP)--are summarized in the review. Despite its name, this peptide does not stimulate sodium excretion but shares the prominent vasodilating and antyproliferating effects in different organs and tissues. The special emphasis is attended to CNP functions in central nervous system. The information about the peptide molecular biology, including intracellular processing, blood peptide concentration, specific receptors structure, and signaling pathways in target cells is presented.

Topics: Animals; Central Nervous System; Humans; Inflammation; Mice; Natriuretic Peptide, C-Type; Rats; Receptors, Atrial Natriuretic Factor; Signal Transduction; Sodium; Vasodilation

The natriuretic peptide system includes three known peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). They contribute to the regulation of cardiovascular homeostasis through diuretic, natriuretic, and vasodilatory properties. Among them, ANP has received particular attention because of its effects on blood pressure regulation and cardiac function. Although the potential for its therapeutic application in the treatment of hypertension and heart failure has been evaluated in several experimental and clinical investigations, no pharmacological approach directly targeted at modulation of ANP levels has ever reached the stage of being incorporated into clinical practice. Recently, ANP has also received attention as being a possible cardiovascular risk factor, particularly in the context of hypertension, stroke, obesity, and metabolic syndrome. Abnormalities in either peptide levels or peptide structure are thought to underlie its implied role in mediating cardiovascular diseases. Meanwhile, BNP has emerged as a relevant marker of left ventricular (LV) dysfunction and as a useful predictor of future outcome in patients with heart failure. This review deals with the major relevant findings related to the cardiovascular and metabolic effects of natriuretic peptides, to their potential therapeutic use, and to their role in mediating cardiovascular diseases.

Topics: Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Fibrosis; Humans; Inflammation; Insulin Resistance; Lipid Metabolism; Myocardium; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Risk Factors; Ventricular Dysfunction, Left; Ventricular Remodeling

C-type natriuretic peptide (CNP) exhibits anti-inflammatory activity besides its natriuretic and diuretic functions. The present study aimed to determine the anticancer and synergistic therapeutic activity of CNP against a 7,12-Dimethylbenz[a]anthracene (DMBA)/Croton oil-induced skin tumor mouse model. CNP (2.5 µg/kg body weight) was injected either alone and/or in combination with Cisplatin (CDDP) (2 mg/kg body weight) for 4 weeks. The dorsal skin tumor incidences/growth and mortality rate were recorded during the experimental period of 16 weeks. The serum C-reactive protein (CRP), and lactate dehydrogenase (LDH) levels, infiltrating mast cells, and AgNORs proliferating cells count were analyzed in control and experimental mice. Further, the expression profile of marker genes of proliferation, inflammation, and progression molecules were analyzed using Reverse transcriptase-polymerase chain reaction (RT-PCR)/quantitative PCR (qPCR), western blot, and immunohistochemistry. The DMBA/Croton oil-induced mice exhibited 100% tumor incidence. Whereas, CNP alone, CDDP alone, and CNP+CDDP combination-treated mice exhibited 58%, 46%, and 24% tumor incidence, respectively. Also, a marked reduction in the levels of serum CRP and LDH, the number of infiltrating mast cells count and AgNORs proliferating cells count were noticed in the mice skin sections. Further, a significant reduction in both mRNA and protein expression levels of proliferation, inflammation, and progression markers were noticed in CNP (p < 0.01), CDDP (p < 0.01), and CNP+CDDP combination (p < 0.001) treated mice, respectively. The results of the present study suggest that CNP has anticancer activity. Further, the CNP+CDDP treatment has more promising anticancer activity as compared with CNP or CDDP alone treatment, probably due to the synergistic antiproliferative and anti-inflammatory activities of CNP and CDDP.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anthracenes; Anti-Inflammatory Agents; Body Weight; Croton; Croton Oil; Inflammation; Mice; Natriuretic Peptide, C-Type; Skin Neoplasms

Amino-terminal pro-C-type natriuretic peptide (NT-proCNP) is the N-terminal fragment of the CNP precursor. NT-proCNP occurs in an equimolar concentration with CNP in human plasma and is considered to be a marker of the extent of CNP biosynthesis. A recent study has shown associations between plasma NT-proCNP and blood pressure; it is also an independent predictor of death and cardiac readmission in people with unstable angina. Beyond that, recent studies have focused on the applicability of assessing NT-proCNP peptide levels in the diagnosis of diseases with different etiologies but the same denominator, i.e., inflammation. This study reviewed recent results on the usability of NT-proCNP peptide levels in the diagnosis of diseases accompanied by statistical analysis of previously reported results. The data obtained confirmed the applicability of the assessment of NT-proCNP levels in biological fluids in diseases, such as Parkinson's disease, sepsis, meningitis, and asthenozoospermia. The reported results demonstrated that NT-proCNP is helpful in a variety of diseases. Furthermore, changes in serum or CSF levels of NT-proCNP reflect only inflammatory states related to general inflammation. Local inflammation does not trigger an increase in NT-proCNP level.

Topics: Biomarkers; Humans; Inflammation; Natriuretic Peptide, C-Type; Peptides; Vasodilator Agents

Inflammation and fibrosis are key mechanisms in cardiovascular remodeling. C-type natriuretic peptide (CNP) is an endothelium-derived factor with a cardiovascular protective role, although its in-vivo effect on cardiac remodeling linked to hypertension has not been investigated. The aim of this study was to determine the effects of chronic administration of CNP on inflammatory and fibrotic cardiac mechanisms in normotensive Wistar rats and spontaneously hypertensive rats (SHR).. Twelve-week-old male SHR and normotensive rats were infused with CNP (0.75 μg/h/100 g) or isotonic saline (NaCl 0.9%) for 14 days (subcutaneous micro-osmotic pumps). Echocardiograms and electrocardiograms were performed, and SBP was measured. After treatment, transforming growth factor-beta 1, Smad proteins, tumor necrosis factor-alpha, interleukin-1 and interleukin-6, nitric oxide (NO) system and 2-thiobarbituric acid-reactive substances were evaluated in left ventricle. Histological studies were also performed.. SHR showed lower cardiac output with signs of fibrosis and hypertrophy in left ventricle, higher NO-system activity and more oxidative damage, as well as higher pro-inflammatory and pro-fibrotic markers than normotensive rats. Chronic CNP treatment-attenuated hypertension and ventricular hypertrophy in SHR, with no changes in normotensive rats. In left ventricle, CNP induced an anti-inflammatory and antifibrotic response, decreasing both pro-fibrotic and pro-inflammatory cytokines in SHR. In addition, CNP reduced oxidative damage as well as collagen content, and upregulated the NO system in both groups.. Chronic CNP treatment appears to attenuate hypertension and associated end-organ damage in the heart by reducing inflammation and fibrosis.

Topics: Animals; Blood Pressure; Heart; Hypertension; Inflammation; Male; Myocardium; Natriuretic Peptide, C-Type; Rats; Rats, Inbred SHR; Rats, Wistar

Our previous study revealed that mice transgenic for endothelial-cell-specific overexpression of CNP (E-CNP Tg mice) are protected against the increased fat weight, inflammation, and insulin resistance associated with high-fat diet (HFD)-induced obesity. In addition, E-CNP overexpression prevented abnormal lipid profiles and metabolism and blocked inflammation in the livers of HFD-fed mice. Because obesity, dyslipidemia, and insulin resistance increase the risk of various liver diseases, including non-alcoholic steatohepatitis (NASH), we here studied the role of E-CNP overexpression in the livers of mice in which NASH was induced through feeding of either HFD or a choline-deficient defined l‑amino-acid diet (CDAA).. Wild-type (Wt) and E-CNP Tg mice were fed either a standard diet or HFD for 25 weeks or CDAA for 10 weeks. We then assessed hepatic and serum biochemistry; measured blood glucose during glucose tolerance test (GTT) and insulin tolerance test (ITT); evaluated hepatic fibrosis and inflammation; and performed hepatic histology and gene expression analysis.. Serum triglycerides, total cholesterol, non-esterified fatty acids, asparagine transaminase, glucose tolerance, and insulin resistance were ameliorated by CNP overexpression in endothelial cells of HFD-fed E-CNP Tg mice. In addition, hepatic fibrosis and inflammation were decreased in HFD-fed E-CNP Tg mice compared with HFD-fed Wt mice. CDAA-fed E-CNP Tg mice showed improved glycemic control, but liver parameters, fibrosis, and inflammation were remained elevated and equivalent to those in CDAA-fed Wt mice.. The overexpression of CNP in endothelial cells has anti-fibrotic and anti-inflammatory effects in liver during HFD-induced NASH in mice.

Topics: Animals; Blood Glucose; Cells, Cultured; Choline Deficiency; Diet, High-Fat; Endothelial Cells; Glucose Tolerance Test; Inflammation; Insulin Resistance; Liver Cirrhosis; Male; Mice; Mice, Transgenic; Natriuretic Peptide, C-Type; Non-alcoholic Fatty Liver Disease

Ageing-related alterations in cardiovascular structure and function are commonly associated with chronic inflammation. A potential blood-based biomarker indicative of a chronic inflammatory state is N-Terminal Pro C-Type Natriuretic Peptide (NTproCNP). We aim to investigate associations between NTproCNP and ageing-related impairments in cardiovascular function. Community-based participants underwent same-day assessment of cardiovascular function and circulating profiles of plasma NTproCNP. Associations between cardiovascular and biomarker profiles were studied in adjusted models including standard covariates. We studied 93 participants (mean age 73 ± 5.3 years, 36 women), of whom 55 (59%) had impaired myocardial relaxation (ratio of peak velocity flow in early diastole E (m/s) to peak velocity flow in late diastole by atrial contraction A (m/s) <0.84). Participants with impaired myocardial relaxation were also found to have lower peak early phase filling velocity (0.6 ± 0.1 vs 0.7 ± 0.1, p < 0.0001) and higher peak atrial phase filling velocity (0.9 ± 0.1 vs 0.7 ± 0.1, p < 0.0001). NTproCNP levelswere significantly lower among participants with impaired myocardial relaxation (16.4% vs 39.5% with NTproCNP ≥ 19, p = 0.012). After multivariable adjustments, NTproCNP was independently associated with impaired myocardial relaxation (OR 2.99, 95%CI 1.12-8.01, p = 0.029). Community elderly adults with myocardial ageing have lower NTproCNP levels compared to those with preserved myocardial function. Given that impaired myocardial relaxation probably represents early changes within the myocardium with ageing, NTproCNP may be useful as an 'upstream' biomarker useful for charting myocardial ageing.

Topics: Aged; Aging; Biomarkers; Blood Flow Velocity; Cardiovascular Diseases; Diastole; Female; Geriatrics; Humans; Inflammation; Male; Myocardium; Natriuretic Peptide, C-Type

The endogenous peptide C-type natriuretic peptide (CNP) binds its receptor, guanylyl cyclase B (GCB), and is expressed by endothelial cells in diverse tissues. Because the endothelial cells of visceral adipose tissue have recently been reported to play a role in lipid metabolism and inflammation, we investigated the effects of CNP on features of obesity by using transgenic (Tg) mice in which CNP was placed under the control of the Tie2 promoter and was thus overexpressed in endothelial cells (E-CNP). Here we show that increased brown adipose tissue thermogenesis in E-CNP Tg mice increased energy expenditure, decreased mesenteric white adipose tissue (MesWAT) fat weight and adipocyte hypertrophy, and prevented the development of fatty liver. Furthermore, CNP overexpression improved glucose tolerance, decreased insulin resistance, and inhibited macrophage infiltration in MesWAT, thus suppressing pro-inflammation during high-fat diet-induced obesity. Our findings indicate an important role for the CNP produced by the endothelial cells in the regulation of MesWAT hypertrophy, insulin resistance, and inflammation during high-fat diet-induced obesity.

Topics: Adipocytes; Animals; Diet, High-Fat; Endothelial Cells; Energy Metabolism; Gene Expression; Glucose Intolerance; Guanylate Cyclase; Inflammation; Insulin Resistance; Liver; Mice; Mice, Transgenic; Natriuretic Peptide, C-Type; Obesity; RNA, Messenger; Thermogenesis

Oxidative stress induced by hemorrhagic shock (HS) initiates a systemic inflammatory response, which leads to subsequent kidney injury. This study assessed the efficacy of c-type natriuretic peptide (CNP) in attenuating kidney injury in a rat model of hemorrhagic shock and resuscitation (HS/R). Sodium pentobarbital-anesthetized adult male Wistar rats underwent HS induced by the withdrawal of blood to a mean arterial pressure of 30-35 mmHg for 50 min. Then, the animals received CNP (25 μg/kg) or vehicle (saline) intravenously, followed byresuscitation with 1.5 times the shed blood volume in the form of normal saline. Mean arterial pressure was measured throughout the experiment, and acid-base status, oxidative stress, inflammation, tissue injury and kidney function were evaluated after resuscitation. CNP infusion reduced the malondialdehyde content, lowered the myeloperoxidase activity and decreased the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the kidney. The histologic injury score and the plasma creatinine concentration were also significantly decreased after CNP treatment compared to the vehicle group. CNP treatment ameliorates oxidative stress, the inflammatory response, and consequently acute kidney injury after HS/R. Thus, CNP may represent a promising strategy to improve resuscitation for the treatment of HS and deserves further investigation.

Topics: Acute Kidney Injury; Animals; Blood Gas Analysis; Cytokines; Disease Models, Animal; Inflammation; Kidney; Lipid Peroxidation; Male; Natriuretic Peptide, C-Type; Neutrophils; Oxidative Stress; Rats, Wistar; Resuscitation; Shock, Hemorrhagic

C-type natriuretic peptide (CNP) exhibits potent anti-inflammatory effects in chondrocytes that have the potential to repair cartilage damage observed in osteoarthritis (OA). However, treatments for OA have been challenging due to poor targeting and delivery of therapeutics. The present study fabricated polyelectrolyte microcapsules loaded with CNP and examined whether the layer-by-layer (LbL) approach could have protective effects in cartilage explants treated with the pro-inflammatory cytokine, interleukin-1β (IL-1β). SEM showed uniform, 2 to 3 μm spherical microcapsules with morphological characteristic similar to templates loaded with or without CNP. The protein was localized around the external surface of the microcapsules with encapsulation efficiencies >82.9%. CNP release profiles were broadly similar following 9 days of culture. The presence of CNP microcapsules did not significantly affect cell viability (80%) with DNA values that remained stable throughout the culture conditions. Confocal imaging showed clustering of microcapsules in chondrocytes to natriuretic peptide receptor (Npr) 2 and 3. Treatment of cartilage explants with CNP microcapsules led to concentration-dependent inhibition of NO release in response to IL-1β and restoration of matrix synthesis. In summary, we demonstrate controlled delivery of CNP to dampen pro-inflammatory effects induced by IL-1β in cartilage explants. The LbL approach has the potential to promote cartilage repair in vivo.

Topics: Animals; Cartilage, Articular; Cattle; Cell Survival; Cells, Cultured; Delayed-Action Preparations; Drug Compounding; Inflammation; Inflammation Mediators; Interleukin-1beta; Natriuretic Peptide, C-Type

There is rapidly growing evidence for the influence of inflammation on the development and progression of Parkinson's disease (PD). N-terminal pro C-type Natriuretic Peptide (NT-proCNP) is a novel potential inflammatory biomarker and has been recently correlated in PD with pro- and anti-inflammatory cytokines, especially TNF-α and IL-10. The study aims to explore serum level of NT-proCNP in group consisted of 132 patients with idiopathic Parkinson's disease (age 59.6±15.l years) and 46 healthy controls (age 58.5±11.5 years). Serum level of NT-proCNP was significantly higher in PD patients than in the control group (p<0.05; PD vs control: mean 3.65±5.5 vs 1.49±0.73, median 1.81 vs 1.46). The serum level of NT-proCNP was directly correlated with the treatment with dopamine agonist (ropinirole) (R=0.38; p<0.05). The higher serum level of NT-proCNP in PD patients being treated with ropinirole suggests a potential proinflammatory characteristic of dopamine agonists.

Topics: Adult; Antiparkinson Agents; Biomarkers; Case-Control Studies; Dopamine Agonists; Female; Humans; Indoles; Inflammation; Male; Middle Aged; Natriuretic Peptide, C-Type; Parkinson Disease

Trypanosoma cruzi, the causative agent of Chagas' disease, induces multiple responses in the heart, a critical organ of infection and pathology in the host. Among diverse factors, eicosanoids and the vasoactive peptide endothelin-1 (ET-1) have been implicated in the pathogenesis of chronic chagasic cardiomyopathy. In the present study, we found that T. cruzi infection in mice induces myocardial gene expression of cyclooxygenase-2 (Cox2) and thromboxane synthase (Tbxas1) as well as endothelin-1 (Edn1) and atrial natriuretic peptide (Nppa). T. cruzi infection and ET-1 cooperatively activated the Ca(2+)/calcineurin (Cn)/nuclear factor of activated T cells (NFAT) signaling pathway in atrial myocytes, leading to COX-2 protein expression and increased eicosanoid (prostaglandins E(2) and F(2α), thromboxane A(2)) release. Moreover, T. cruzi infection of ET-1-stimulated cardiomyocytes resulted in significantly enhanced production of atrial natriuretic peptide (ANP), a prognostic marker for impairment in cardiac function of chagasic patients. Our findings support an important role for the Ca(2+)/Cn/NFAT cascade in T. cruzi-mediated myocardial production of inflammatory mediators and may help define novel therapeutic targets.

Topics: Animals; Atrial Natriuretic Factor; Calcineurin; Calcium; Cyclooxygenase 2; Endothelin-1; Gene Expression Profiling; Inflammation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Monocytes; Myocytes, Cardiac; Natriuretic Peptide, C-Type; NFATC Transcription Factors; Protein Precursors; Signal Transduction; Thromboxane-A Synthase; Trypanosoma cruzi

C-type natriuretic peptide (CNP) is a paracrine growth factor critical in endochondral bone growth. Amino-terminal CNP (NTproCNP), measurable in plasma, correlates with growth-plate activity and can be used as a biomarker of growth velocity in children. Because severe inflammation in adults increases CNP, we studied CNP peptides and inflammatory markers in children with acute illness.. Forty-two children aged 2 mo to 5 y with acute illness warranting admission to an acute assessment unit were studied. Fifteen age-matched healthy children attending an outpatient clinic served as controls. Venous CNP concentrations were measured at admission, along with markers of acute inflammation (body temperature, C-reactive protein (CRP), and white blood cell count) in children with acute illness.. NTproCNP and CNP SD scores (SDSs) in the acutely ill group were significantly suppressed (P < 0.001) as compared with those of healthy children or healthy population norms. NTproCNP SDS was significantly inversely related to body temperature (r = -0.42, P < 0.01) and CRP (r = -0.56, P < 0.001).. Acute inflammation in young children potently reduces CNP production, which needs to be considered when screening for growth disorders. Our data raise the possibility that the adverse effects of inflammatory cytokines on skeletal growth may be mediated in part by reduced CNP.

Topics: Body Temperature; C-Reactive Protein; Case-Control Studies; Child, Preschool; Humans; Infant; Inflammation; Leukocyte Count; Natriuretic Peptide, C-Type

The role of inflammatory factors in Parkinson's disease (PD) has not been consistently proven yet. Despite the presence of some potentially causative factors, the primary and initiating factor has not been determined. Therefore the influence of proinflammatory and antiphlogistic factors on the risk of PD remains unclear. The aim of the study was to evaluate the level of NT-proCNP as well as proinflammatory factors in peripheral blood of patients with PD and to compare the changes of cytokines and NT-proCNP profile of these patients with the profile within the control group.. The study group consisted of 60 patients with the diagnosis of idiopathic PD, in the mean age of 59 ± 15.5 years, and control group of 24 persons, in the mean age of 64 ± 5.8 years, without neurodegenerative and inflammatory disorders. The quantitative determination of cytokines was evaluated with the fluorokine MAP cytokine multiplex kit and the Luminex 100 Platform. ELISA kits were used for the quantitative determination of human NT-proCNP.. The levels of NT-proCNP and all measured cytokines were higher in serum of PD patients in comparison to the control group, though the significant differences were only observed in relation to serum level of NT-proCNP (p<0.05) and TNF-α (p<0.001). The mean serum level of NT-proCNP in PD patients correlates with the level of TNF-α (R=0.359, p<0.05) and IL-10 (R=-0.39, p=0.05). There are also other correlations in serum of PD group: between IL-10 and IL-12 (R=0.39, p=0.05), IL-6 and IL-1ß (R=0.65, p=0.05). The serum level of IL-6 is also in a positive relation with H&Y stage (R=0.27, p=0.05).. The concentration of NT-proCNP and TNF-α is essentially higher in parkinsonian patients than in healthy group. The levels of other anti- and proinflammatory cytokines also tend to be higher in PD patients in comparison to the control group. It confirms the significance of these factors' influence on molecular pathogenesis of PD and makes NT-proCNP a new potential determinant of inflammation in PD patients.

Topics: Cytokines; Female; Humans; Inflammation; Male; Middle Aged; Natriuretic Peptide, C-Type; Parkinson Disease

Inflammation involves the cooperation of various cells and biologically active molecules. An important intracellular messenger molecule participating in the regulation of the process is cyclic GMP (cGMP), which is synthesized by guanylyl cyclases (GCs). The GC family comprises cytosolic (soluble) and membrane-bound (particulate) enzymes. The aim of this study was to determine whether and how the synthesis of cGMP by various forms of GC affects the expression of inflammatory cytokines depending on the activity of the transcription factors NF-κB (nuclear factor-κB) and AP-1 (activator protein-1). We established that in rat peripheral blood mononuclear cells (PBMCs), synthesis of cGMP was elevated by sodium nitroprusside (SNP), the activator of soluble GC, and by atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP), the activators of particulate GC-A and GC-B, respectively. Stimulation of various GCs differently affected the expressions of the cytokines IL-1β, IL-6, and TNF-α in control cells and in cells activated by bacterial endotoxin (LPS). In control PBMCs their expression was elevated by stimulation of soluble, but not particulate, GC. SNP caused an increase in NF-κB activity, but had no influence on the activity of AP-1. The cells treated with LPS decreased the expressions of IL-1β, IL-6, and TNF-α in response to stimulation of particulate GC-A, but not other guanylyl cyclases. This inhibitory effect was a result of suppression of the activities of NF-κB and AP-1. Both effects that of SNP and of ANP, were cGMP dependent, as shown using its membrane-permeable analog 8-Br-cGMP. The implementation of specific inhibitors showed that the stimulatory effect of SNP was mediated by soluble GC and cGMP-dependent protein kinase (PKG-I). However, PKG-I was not involved in the inhibition of NF-κB and AP-1 activities by ANP in LPS-activated cells. Taken together, these results for the first time indicate that various GCs and various cGMP-dependent signaling pathways can modulate the activity of AP-1 and/or NF-κB and thus affect the expressions of IL-1β, IL-6, and TNF-α, which play important roles in the development of inflammation.

Topics: Animals; Atrial Natriuretic Factor; Blotting, Western; Cyclic GMP; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic GMP-Dependent Protein Kinases; Cytokines; Electrophoretic Mobility Shift Assay; Gene Expression Regulation; Guanylate Cyclase; Inflammation; Leukocytes, Mononuclear; Lipopolysaccharides; Natriuretic Peptide, C-Type; Nitroprusside; Rats; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Solubility; Transcription Factor AP-1

Myocarditis is an acute inflammatory disease of the myocardium for which there is currently no specific therapy. We investigated the therapeutic potential of C-type natriuretic peptide (CNP) in acute experimental autoimmune myocarditis. One week after injection of porcine myosin into male Lewis rats, CNP (0.05 microg/kg/min) was continuously administered for 2 weeks. CNP infusion significantly increased maximum dP/dt, decreased left ventricular end-diastolic pressure, and improved fractional shortening compared with vehicle administration. In vehicle-treated hearts, severe necrosis and marked infiltration of CD68-positive inflammatory cells were observed. Myocardial and serum levels of monocyte chemoattractant protein-1 were elevated in myocarditis. However, these changes were attenuated by CNP infusion. In addition, treatment with CNP significantly increased myocardial capillary density. Guanylyl cyclase-B, a receptor for CNP, was expressed in myocarditic heart, and cyclic guanosine monophosphate was elevated by CNP infusion. In conclusion, CNP infusion attenuated cardiac function in acute myocarditis through anti-inflammatory and angiogenic effects.

Topics: Animals; Blood Pressure; Blood Vessels; Chemokine CCL2; Cyclic GMP; Enzyme-Linked Immunosorbent Assay; Guanylate Cyclase; Heart; Heart Rate; Inflammation; Male; Myocarditis; Myocardium; Natriuretic Agents; Natriuretic Peptide, C-Type; Radioimmunoassay; Rats; Rats, Inbred Lew; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Swine; Ultrasonography; von Willebrand Factor

The multifaceted process of immune cell recruitment to sites of tissue injury is key to the development of an inflammatory response and involved in the pathogenesis of numerous cardiovascular disorders. We recently identified C-type natriuretic peptide (CNP) as an important endothelium-derived mediator that regulates vascular tone and protects against myocardial ischemia/reperfusion injury. Herein, we investigated whether CNP inhibits leukocyte recruitment and platelet aggregation and thereby exerts a potential antiinflammatory influence on the blood vessel wall. We assessed the effects of CNP on leukocyte-endothelial cell interactions in mouse mesenteric postcapillary venules in vivo in animals with high basal leukocyte activation (endothelial nitric oxide synthase knockout mice, eNOS(-/-)) or under acute inflammatory conditions (induced by interleukin-1beta or histamine). CNP suppressed basal leukocyte rolling in eNOS(-/-) mice in a rapid, reversible, and concentration-dependent manner. These effects of CNP were mimicked by the selective natriuretic peptide receptor-C agonist cANF(4-23). CNP also suppressed leukocyte rolling induced by IL-1beta or histamine, inhibited platelet-leukocyte interactions, and prevented thrombin-induced platelet aggregation of human blood. Furthermore, analysis of human umbilical vein endothelial cells, leukocytes, and platelets revealed that CNP selectively attenuates expression of P-selectin. Thus, CNP is a modulator of acute inflammation in the blood vessel wall characterized by leukocyte and platelet activation. These antiinflammatory effects appear to be mediated, at least in part, via suppression of P-selectin expression. These observations suggest that endothelial CNP might maintain an anti-atherogenic influence on the blood vessel wall and represent a target for therapeutic intervention in inflammatory cardiovascular disorders.

Topics: Analysis of Variance; Animals; Atrial Natriuretic Factor; Endothelium, Vascular; Flow Cytometry; Gene Expression Regulation; Humans; Inflammation; Leukocytes; Mice; Mice, Knockout; Natriuretic Peptide, C-Type; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; P-Selectin; Peptide Fragments; Platelet Aggregation; Venules

Natriuretic peptides (NPs), which consist of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP, respectively), are characterized as cardiac or vascular hormones that elicit their biological effects by activation of the cGMPcGMP-dependent protein kinase (cGK) pathway. We recently reported that adenoviral gene transfer of CNP into rabbit blood vessels not only suppressed neointimal formation but also accelerated reendothelialization, a required step for endothelium-dependent vasorelaxation and antithrombogenicity. Accordingly, we investigated the therapeutic potential of the NPscGMPcGK pathway for vascular regeneration. In transgenic (Tg) mice that overexpress BNP in response to hindlimb ischemia, neovascularization with appropriate mural cell coating was accelerated without edema or bleeding, and impaired angiogenesis by the suppression of nitric oxide production was effectively rescued. Furthermore, in BNP-Tg mice, inflammatory cell infiltration in ischemic tissue and vascular superoxide production were suppressed compared with control mice. Ischemia-induced angiogenesis was also significantly potentiated in cGK type I Tg mice, but attenuated in cGK type I knockout mice. NPs significantly stimulated capillary network formation of cultured endothelial cells by cGK stimulation and subsequent Erk12 activation. Furthermore, gene transfer of CNP into ischemic muscles effectively accelerated angiogenesis. These findings reveal an action of the NPscGMPcGK pathway to exert multiple vasculoprotective and regenerative actions in the absence of apparent adverse effects, and therefore suggest that NPs as the endogenous cardiovascular hormone can be used as a strategy of therapeutic angiogenesis in patients with tissue ischemia.

Topics: Animals; Atrial Natriuretic Factor; Blood Vessels; Cells, Cultured; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Gene Expression; Gene Transfer Techniques; Humans; Inflammation; Ischemia; Mice; Mice, Knockout; Mice, Transgenic; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Neovascularization, Physiologic; Regeneration

We previously observed that adenovirus-mediated expression of C-type natriuretic peptide (CNP) markedly inhibits neointima formation after balloon injury in rat carotid arteries, suggesting that CNP has multiple effects over its modest inhibitory effect on cellular proliferation. We hypothesized that local expression of CNP might have antithrombotic and antiinflammatory effects. Balloon-injured rabbit carotid arteries were infected with an adenovirus expressing human CNP (AdCNP), human tissue factor pathway inhibitor (AdTFPI), or bacterial beta-galactosidase (AdLacZ) or infused with saline. Seven days later, shear stress-induced thrombosis was evaluated by cyclic flow variation (CFV), reflecting recurrent cycles of thrombus formation and dislodgment. CFV was observed in all AdLacZ-infected and saline-infused arteries but not in arteries infected with AdCNP or AdTFPI even in the presence of epinephrine. Injury increased the expressions of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and infiltration of macrophages. However, these effects were markedly reduced in AdCNP-treated arteries but not in AdTFPI-infected ones. In AdCNP-infected arteries, injury-induced expression of inducible NO synthase (iNOS) was enhanced, leading to increased NO generation. Interestingly, when the enhanced NO production was inhibited, neither inhibitory effect was observed, and suppression of neointima formation by CNP was canceled. Our study demonstrates that overexpression of CNP shows antithrombotic and antiinflammatory effects and reduces neointima formation mainly through enhanced NO production.

Topics: Adenoviridae; Animals; beta-Galactosidase; Blood Flow Velocity; Carotid Arteries; Carotid Artery Thrombosis; Disease Models, Animal; Enzyme Inhibitors; Genes, Reporter; Genetic Therapy; Genetic Vectors; Humans; Inflammation; Intercellular Adhesion Molecule-1; Lipoproteins; Macrophages; Male; Natriuretic Peptide, C-Type; Nitric Oxide; Rabbits; Rats; Rats, Wistar; Stress, Mechanical; Tunica Intima; Vascular Cell Adhesion Molecule-1; Vasoconstrictor Agents