Brain Natriuretic Peptide Treatment Research Articles

Brain Natriuretic Peptide Protects Cardiomyocytes from Apoptosis and Stimulates Their Cell Cycle Re-Entry in Mouse Infarcted Hearts.

Brain Natriuretic Peptide (BNP) supplementation after infarction increases heart function and decreases heart remodeling. BNP receptors, NPR-A and NPR-B are expressed on adult cardiomyocytes (CMs). We investigated whether a part of the BNP cardioprotective effect in infarcted and unmanipulated hearts is due to modulation of the CM fate. For this purpose, infarcted adult male mice were intraperitoneally injected every two days during 2 weeks with BNP or saline. Mice were sacrificed 1 and 14 days after surgery. BNP or saline was also injected intraperitoneally every two days into neonatal pups (3 days after birth) for 10 days and in unmanipulated 8-week-old male mice for 2 weeks. At sacrifice, CMs were isolated, counted, measured, and characterized by qRT-PCR. The proportion of mononucleated CMs was determined. Immunostainings aimed to detect CM re-entry in the cell cycle were performed on the different hearts. Finally, the signaling pathway activated by BNP treatment was identified in in vitro BNP-treated adult CMs and in CMs isolated from BNP-treated hearts. An increased number of CMs was detected in the hypoxic area of infarcted hearts, and in unmanipulated neonatal and adult hearts after BNP treatment. Accordingly, Troponin T plasma concentration was significantly reduced 1 and 3 days after infarction in BNP-treated mice, demonstrating less CM death. Furthermore, higher number of small, dedifferentiated and mononucleated CMs were identified in adult BNP-treated hearts when compared to saline-treated hearts. BNP-treated CMs express higher levels of mRNAs coding for hif1 alpha and for the different cyclins than CMs isolated from saline-treated hearts. Higher percentages of CMs undergoing DNA synthesis, expressing Ki67, phospho histone3 and Aurora B were detected in all BNP-treated hearts, demonstrating that CMs re-enter into the cell cycle. BNP effect on adult CMs in vivo is mediated by NPR-A binding and activation of the ERK MAP kinase pathway. Interestingly, an increased number of CMs was also detected in adult infarcted hearts treated with LCZ696, an inhibitor of the natriuretic peptide degradation. Altogether, our results identified BNP and all therapies aimed to increase BNP's bioavailability as new cardioprotective targets as BNP treatment leads to an increased number of CMs in neonatal, adult unmanipulated and infarcted hearts.

Effects of Recombinant Human Brain Natriuretic Peptide in Patients with Acute Pulmonary Embolism Complicated with Right Ventricular Dysfunction Who Underwent Catheter-Directed Therapy.

Acute pulmonary embolism (PE) remains a significant cause of cardiovascular morbidity and mortality worldwide. Brain natriuretic peptide (BNP) combined with catheter-directed therapy (CDT) may improve right ventricular (RV) dysfunction and stabilize hemodynamics in acute PE.We retrospectively studied 159 patients with confirmed acute PE who were treated with CDT and admitted to the intensive care unit of our department between September 2016 and May 2020. The patients were divided into the control group and the rhBNP group based on whether to receive recombinant human BNP treatment (rhBNP) or not. The basic characteristics of the patients between the control group and the rhBNP group was systematically compared during admission and follow-up. Risk factors for all-cause mortality within 30 days were determined using multivariate logistic regression analysis.Respiratory rate was found to be significantly lower in the rhBNP group than in the control group. Patients in the rhBNP group had significantly lower levels of white blood cell, C-reactive protein (CRP), D-dimers, troponin I, creatinine, and N-terminal (NT) -proBNP compared with those in the control group. Levels of tricuspid annular plane systolic excursion were significantly higher in the rhBNP group than in the control group. The percentage of patients with rehospitalization readmission due to PE differed significantly between the control group and the rhBNP group. On the basis of the multivariate regression analysis, CRP, creatinine, troponin I, and NT-proBNP were independent factors of all-cause mortality in 30 days.rhBNP is effective in the treatment of patients with RV dysfunction caused by acute PE who underwent CDT, which may be an alternative treatment option for improving clinical prognosis.

Increasing heart vascularisation after myocardial infarction using brain natriuretic peptide stimulation of endothelial and WT1+ epicardial cells.

Brain natriuretic peptide (BNP) treatment increases heart function and decreases heart dilation after myocardial infarction (MI). Here, we investigated whether part of the cardioprotective effect of BNP in infarcted hearts related to improved neovascularisation. Infarcted mice were treated with saline or BNP for 10 days. BNP treatment increased vascularisation and the number of endothelial cells in all areas of infarcted hearts. Endothelial cell lineage tracing showed that BNP directly stimulated the proliferation of resident endothelial cells via NPR-A binding and p38 MAP kinase activation. BNP also stimulated the proliferation of WT1+ epicardium-derived cells but only in the hypoxic area of infarcted hearts. Our results demonstrated that these immature cells have a natural capacity to differentiate into endothelial cells in infarcted hearts. BNP treatment increased their proliferation but not their differentiation capacity. We identified new roles for BNP that hold potential for new therapeutic strategies to improve recovery and clinical outcome after MI.

BNP increases the number of cardiomyocytes in physiological and pathological conditions

Brain natriuretic peptide (BNP) treatment protects the heart after myocardial infarction (MI). As cardiomyocytes (CMs) express BNP receptors, the aim of this study was to determine BNP effect on CM's fate in neonatal and in adult infarcted hearts. New born (NB) unmanipulated pups and adult infarcted mice were injected with BNP every 2 days. NB mice were sacrificed eleven days after birth. MI was induced in C57BL/6 and Myh6 MerCreMer mice by permanent ligation of the left anterior descending coronary artery and sacrificed 24 hours and 10 days after surgery. An increased number of CMs was detected in BNP-treated NB mice (+ 18% P = 0.002) and in the infarcted zone (ZI) of adult hearts, 10 days after MI (+ 43%; P = 0.07). In BNP-treated pups, the number of CMs expressing BrdU (+ 22% P = 0.04), phospho histone H3 (pH3) (+ 31%; P = 0.04) and Aurora B (+ 47% P = 0.001) were increased. Expressions of mRNAs coding for cyclins E1 (+ 110% P = 0.01), A2 (+ 126% P = 0.002) and B2 (+70% P = 0.08) were increased in CMs isolated from BNP treated hearts. Accordingly, in vitro BNP treatment of neonatal CMs led to increased number of CMs (+ 21% P = 0.003), and CMs expressing Aurora B (+ 58% P = 0.01), pH3 (+ 75% P = 0.04) or Ki67 (+ 20% P = 0.03). Interestingly, BNP treatment on these cells was associated with p38 MAPK inhibition (-42% P = 0.01). In BNP-treated mice 24 hours after MI, a decreased concentration of cardiac Troponin T in the plasma (− 70% P = 0.04) was measured, whereas the percentage of BrdU+ (+ 92% P = 0.03), pH3+ (+ 51%; n = 2) and Aurora B+ CMs (+ 419% P = 0.03) increased in ZI of BNP-treated hearts, 10 days after MI. In Myh6 MerCreMer mice, the percentage of GFP+ CMs expressing BrdU also increased in ZI (+ 15% P < 0.05). In conclusion, BNP treatment protects CMs from cell death after MI. In addition, it stimulates the proliferation of neonatal and adult pre-existing CMs after MI.

BNP modulates cardiomyocyte proliferation in vitro and in vivo

Brain natriuretic peptide (BNP) treatment protects the heart after myocardial infarction (MI). As cardiomyocytes (CMs) express BNP receptors, the aim of this study was to determine the role of BNP on CM proliferation. We studied the BNP effect on the hearts of new born (NB) and adult infarcted mice. NB mice were injected with BNP and with BrdU two days after birth and sacrificed after eleven days. MI was induced by ligation of the left anterior descending coronary artery. BNP was injected directly into the myocardium after surgery, then intraperitoneally every 2 days. BrdU was added to drinking water. Mice were sacrificed 3 and 10 days after surgery. The infarction zone (ZI) was separated from the rest of the heart (remote zone, RZ). The number of CMs expressing BrdU + (+ 22% P = 0.04) or Aurora B+ (+ 47% P = 0.001) was increased in NB BNP-treated mice compared to the control, leading to increased number of CMs (+ 21%). Expressions of mRNAs coding for the cyclins were also increased in isolated cardiomyocytes from BNP treated hearts: cyclin E1 (+ 110% P = 0.01), A2 (+ 126% P = 0.002) and B2 (+ 70% P = 0.08). In adult infarcted mice, 3 and 10 days after MI, BNP stimulation induced an increased number of BrdU+ CMs and Aurora B + CMs in ZI (3 days: + 172% P < 0.001 and +69% P = 0.01, respectively, 10 days: + 102% P < 0.001 and + 127% P = 0.008, respectively). In parallel, CMs were isolated from NB hearts and cultured with or without BNP. After two weeks of culture, BNP treatment led to increased number of CMs (+ 21% P = 0.003), CMs expressing Aurora B (+ 58% P = 0.01), phospho-histone H3 (+ 75% P = 0.04) and Ki67 (+ 20% P = 0.03). BNP decreased CM binucleation (− 32% P = 0.001). Interestingly, BNP stimulation of CM proliferation in vitro seems to be trigger by the p38 MAPK pathway inhibition (− 42% P = 0.01). BNP treatment leads to increased number of proliferating CMs in vivo in NB hearts and in adult hearts after MI. Whether this reflects an increase of cytokinesis remains to be established in vivo.

Does BNP modulate cardiomyocyte proliferation?

Brain natriuretic peptide (BNP) treatment protects the heart after myocardial infarction (MI). As cardiomyocytes (CMs) express BNP receptors, the aim of this study was to determine the role of BNP on CM proliferation. We studied the BNP effect on the hearts of newborn (NB) and adult infarcted mice. NB mice were injected with BNP and with BrdU two days after birth. Eleven days post-birth, the mice were sacrificed. MI was induced by ligation of the left anterior descending coronary artery. BNP was injected directly into the myocardium after surgery, then intraperitoneally every 2 days up to 10 days. BrdU was added to drinking water. Mice were sacrificed 3 and 10 days after surgery. The infarction zone (ZI) was separated from the rest of the heart (remote zone, RZ). The number of CMs expressing BrdU + (+22%, P = 0.04) or Aurora B + (+47%, P = 0.001) was increased in NB BNP-treated mice compared to the control. In addition, the total number of CMs was also increased (+21%) in BNP-treated mice. After MI, the number of BrdU + CMs and the number of Aurora B + CMs were increased in ZI, 3 days after MI in BNP-treated hearts compared to the infarcted untreated hearts (+172%, P < 0.001; +69%, P = 0.01, respectively). This seems to be also the case 10 days after MI in ZI for the BrdU + CMs (preliminary results: +194%, n = 2 mice/group). In parallel, we isolated CMs from the hearts of NB. These cells were cultured with or without BNP. After two weeks of culture with BNP, the number of Aurora B + CMs increased (+87%, P = 0.003) but not the number of binucleated CMs. In addition, among Aurora B + CMs, BNP increased the number of cells undergoing cytokinesis (+6%). Interestingly, the total number of CMs was increased in BNP-treated cells compared to control (+26%, P = 0.01). BNP treatment leads to increased number of Aurora B + CMs in vivo in NB hearts, and in adult hearts after MI. This was confirmed by in vitro studies. Whether this reflects an increase of cytokinesis remains to be established in vivo.

Natriuretic Peptide Receptor B modulates the proliferation of the cardiac cells expressing the Stem Cell Antigen-1

Brain Natriuretic Peptide (BNP) injections in adult “healthy” or infarcted mice led to increased number of non-myocyte cells (NMCs) expressing the nuclear transcription factor Nkx2.5. The aim of this study was to identify the nature of the cells able to respond to BNP as well as the signaling pathway involved. BNP treatment of neonatal mouse NMCs stimulated Sca-1+ cell proliferation. The Sca-1+ cells were characterized as being a mixed cell population involving fibroblasts and multipotent precursor cells. Thus, BNP treatment led also to increased number of Sca-1+ cells expressing Nkx2.5, in Sca-1+ cell cultures in vitro and in vivo, in the hearts of neonatal and adult infarcted mice. Whereas BNP induced Sca-1+ cell proliferation via NPR-B receptor and protein kinase G activation, CNP stimulated Sca-1+ cell proliferation via NPR-B and a PKG-independent mechanism. We highlighted here a new role for the natriuretic peptide receptor B which was identified as a target able to modulate the proliferation of the Sca-1+ cells. The involvement of NPR-B signaling in heart regeneration has, however, to be further investigated.

Brain natriuretic peptide for prevention of contrast-inducednephropathy: a meta-analysis of randomized controlled trials.

Contrast-induced nephropathy (CIN) is a serious complication and associated with poor clinical outcomes. The protective value of brain natriuretic peptide (BNP) administration on CIN is still controversial in patients undergoing percutaneous coronary intervention (PCI) or coronary angiography (CAG). We performed a meta-analysis of randomized controlled trials (RCTs) for BNP in preventing CIN. We systematically searched PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov for RCTs comparing administration of BNP versus non-BNP for preventing CIN. Publication bias was assessed by funnel plots. Relative risk (RR) was calculated for incidence of CIN and major adverse cardiovascular events (MACEs) using the random or fixed effect model according to heterogeneity analysis. There were five RCTs with 1441 patients in this analysis. BNP treatment was associated with lower incidence of CIN (RR=0.38, 95% CI 0.27-0.54, p<0.001) and MACEs (RR=0.47, 95% CI 0.24-0.95, p=0.034) with no significant heterogeneity (I 2=0%, p=0.701; I 2=60%, p=0.113, respectively). Similar results were seen in subgroup analysis. Prophylactic BNP significantly decreased the incidence of CIN after cardiac catheterization in the studies of regarding sodium chloride as placebo (I 2=0%, RR=0.39, 95% CI 0.27-0.56, p<0.001) or JADAD score>3 (I 2=0%, RR=0.38, 95% CI 0.21-0.68, p=0.001). Preprocedural BNP treatment significantly decreased the incidence of CIN and short-term MACEs in patients undergoing PCI or CAG.

0006 : Proliferation of the cardiac precursor cells expressing the stem cell antigen-1 is controlled by activation of the natriuretic peptide receptors

A part of the cardioprotective role of the Brain Natriuretic Peptide (BNP) in mouse hearts is due to its effect on the cardiac precursor cell (CPC) proliferation and differentiation. Thus, in this study we identified the CPC subset able to respond to BNP as well as the signaling pathway involved. We demonstrated by immunohistochemistry and by flow cytometry analysis that the c-kit + and the Sca-1 + cell subsets in neonatal and adult murine hearts express the NPR-A and NPR-B receptors and are thus able to be stimulated by BNP. In vitro , BNP only stimulated the proliferation of the Sca-1 + cells and not of the c-kit + cells. Among Sca-1 + cells, BNP treatment led to increased number of Sca-1 + Nkx2.5 + cells, which were able to differentiate into cardiomyocytes. To determine by which receptor BNP acts on Sca-1 + cells to stimulate their proliferation, cells were isolated from neonatal hearts of mice deficient for the NPR-A (NPRA-KO) or NPR-B receptor. BNP stimulated the proliferation of the Sca-1 + NPR-A KO cells but not of the Sca-1 + cells lacking the NPR-B receptor, demonstrating that Sca-1 + cell proliferation is linked to NPR-B activation. This was confirmed by stimulating the Sca-1 + cells by the C-Natriuretic Peptide able also to activate the NPR-B receptor. BNP binding to NPR-B receptor led in Sca-1 + cells to Protein Kinase G activation and increased phosphorylation of phospholamban and p38. Reducing PKG activation inhibited BNP-induced-Sca-1 + cell proliferation, whereas reducing p38 phosphorylation increased Sca-1 + cell proliferation after BNP treatment. Phosphorylation of p38 was not mediated by BNP binding to NPR-B receptor but by its binding to NPR-A. In this work, we identified the Sca-1 + cells as being the targets of BNP in vitro and in vivo. BNP via NPR-B binding and PKG activation clearly stimulated the proliferation of the CPCs expressing Sca-1. Interestingly, is the dual role of the NPR-A and NPR-B receptors which control Sca-1 + cell proliferation. The author hereby declares no conflict of interest

0128 : Sca-1 positive cells, but not c-kit positive cells, differentiate into mature cardiomyocytes after brain natriuretic peptide treatment

The Brain Natriuretic Peptide (BNP) is a cardiac hormone, which promotes the recovery of cardiac function and the preservation of cardiac tissue in animal models of heart diseases. Its cardiac protective role in animals was attributed to fibrosis inhibition, as well as to reduction of cardiomyocyte apoptosis and hypertrophy. Recently, we demonstrated that BNP induces heart regeneration via the stimulation of cardiac precursor cell (CPC) proliferation and differentiation into mature cardiomyocytes. The aim of our study was to identify which CPC’s subset is able to respond to BNP stimulation. Cardiac precursor cells identified as being Sca-1 + Nkx2.5 + or c-kit + Nkx2.5 + cells, expressed in neonatal and adult hearts BNP’s receptors (NPR-A and NPR-B), showing their ability to be activated by BNP treatment. Cell sorting experiments based on the expression of Sca-1 or c-kit were performed on nonmyocyte cells isolated from neonatal wild-type hearts. Sca-1 + and c-kit + cells were cultured up to 3 weeks with or without BNP in differentiating medium. Sca-1 positive cells, which contained few c-kit + cells, responded clearly to BNP stimulation by upregulating mRNA levels of genes coding for Nkx2.5, Mlc-2v, c-kit, Sca-1, beta and alpha MHC. Furthermore, higher number of Troponin I + cells was detected in BNP treated cells compared to untreated cells, suggesting that Sca-1 + cells differentiated after BNP stimulation into mature cardiomyocytes. BNP treatment of c-kit + cells didn’t induce the upregulation of mRNA coding for cardiomyocyte specific genes. However, we determined that c-kit positive cells spontaneously differentiated into mature cardiomyocytes during the 3 weeks of cell culture without BNP stimulation. To determine which receptor is involved, Sca-1 + cells, isolated from neonatal hearts of NPR-A or NPR-B deficient mice, were treated with BNP. The effects of BNP on wild type and NPR-A KO cells did not differ substantially. However, Sca-1 + cells isolated from NPR-B deficient hearts couldn’t respond anymore to BNP stimulation. Thus, BNP specifically stimulates via NPR-B Sca-1 + cell differentiation into cardiomyocytes. c-kit + cells display clearly a cardiogenic potential which is BNP independent.

Brain natriuretic peptide is able to stimulate cardiac progenitor cell proliferation and differentiation in murine hearts after birth.

Brain natriuretic peptide (BNP) contributes to heart formation during embryogenesis. After birth, despite a high number of studies aimed at understanding by which mechanism(s) BNP reduces myocardial ischemic injury in animal models, the actual role of this peptide in the heart remains elusive. In this study, we asked whether BNP treatment could modulate the proliferation of endogenous cardiac progenitor cells (CPCs) and/or their differentiation into cardiomyocytes. CPCs expressed the NPR-A and NPR-B receptors in neonatal and adult hearts, suggesting their ability to respond to BNP stimulation. BNP injection into neonatal and adult unmanipulated mice increased the number of newly formed cardiomyocytes (neonatal: +23 %, p = 0.009 and adult: +68 %, p = 0.0005) and the number of proliferating CPCs (neonatal: +142 %, p = 0.002 and adult: +134 %, p = 0.04). In vitro, BNP stimulated CPC proliferation via NPR-A and CPC differentiation into cardiomyocytes via NPR-B. Finally, as BNP might be used as a therapeutic agent, we injected BNP into mice undergoing myocardial infarction. In pathological conditions, BNP treatment was cardioprotective by increasing heart contractility and reducing cardiac remodelling. At the cellular level, BNP stimulates CPC proliferation in the non-infarcted area of the infarcted hearts. In the infarcted area, BNP modulates the fate of the endogenous CPCs but also of the infiltrating CD45(+) cells. These results support for the first time a key role for BNP in controlling the progenitor cell proliferation and differentiation after birth. The administration of BNP might, therefore, be a useful component of therapeutic approaches aimed at inducing heart regeneration.

0232: A new role of the brain natriuretic peptide in the heart: Modulation of cardiac precursor cell proliferation and differentiation

The actual role of the brain natriuretic peptide (BNP) in the heart remains elusive despite its reported protective effect in ischemic animal hearts. Because recently BNP was shown to control the proliferation and differentiation of murine embryonic stem cells, we asked in this study whether BNP could influence the proliferation and differentiation of cardiac progenitor cells (CPC) in vitro and in vivo . We first identified a c-kit + Sca-1 + cell population present in neonatal and adult hearts which expressed the NPR-A and NPR-B receptors. In vitro, these cells proliferated and in presence of BNP differentiated into CPCs (c-kit + Sca-1 + Nkx2.5 + ) and into mature cardiomyocytes. In parallel, BNP was injected to newborn and adult healthy mice (n=6 mice per group). In the hearts of both neonatal and adult mice, BNP injection increased the number of newly formed cardiomyocytes (neonatal: + 23%, p= 0.009 and adult: +68%, p= 0.005) and the number of CPCs (neonatal: + 142%, p= 0.002 and adult: +134%, p= 0.04). BrdU injection to neonatal BNP treated mice demonstrated that BNP stimulated CPC proliferation. In anticipation that BNP might be used as a therapeutic agent, we injected BNP into mice undergoing myocardial infarction (n=6-7 mice per group). Higher numbers of Nkx2.5+ cells were detected in both the infarcted (+38%, p=0.03) and non infarcted areas (+69%, p=0.02) of BNP treated hearts one week after surgery. Finally, by isolating neonatal cardiac cells from the hearts of NPR-A or NPR-B deficient mice, we demonstrated that BNP modulates the fate of CPCs via NPRB binding and that long term BNP treatment is correlated in vitro and in vivo with decreased Protein Kinase G activity. Our results highlight a new key role for BNP in the control of CPC proliferation and/or differentiation. This new function of BNP should be evaluated in therapies aimed to induce cardiac cell regeneration and should reopen the debate about the therapeutic use of BNP for patients suffering from heart diseases.

Treatment with brain natriuretic peptide prevents the development of cardiac dysfunction in obese diabetic db/db mice

Obesity and diabetes increase the risk of developing cardiovascular diseases and heart failure. These metabolic disorders are generally reflected by natriuretic peptide system deficiency. Since brain natriuretic peptide (BNP) is known to influence metabolism and cardioprotection, we investigated the effect of chronic exogenous BNP treatment on adverse myocardial consequences related to obesity and diabetes. Ten-week-old C57BL/KsJ-db/db obese diabetic mice (db/db) and their lean control littermates (db/+) were treated with BNP (0.6 μg kg(-1) h(-1)) or saline for 12 weeks (n = 10/group). Serial blood and tomography analysis were performed. Cardiac function was determined by echocardiography, and biochemical and histological heart and fat analyses were also performed. BNP treatment resulted in an average increase in plasma BNP levels of 70 pg/ml. An improvement in the metabolic profile of db/db mice was observed, including a reduction in fat content, increased insulin sensitivity, improved glucose tolerance and lower blood glucose, despite increased food intake. db/db mice receiving saline displayed both early systolic and diastolic dysfunction, whereas these functional changes were prevented by BNP treatment. The cardioprotective effects of BNP were attributed to the inhibition of cardiomyocyte apoptosis, myocardial fibrosis, cardiac hypertrophy and the AGE-receptor for AGE (RAGE) system as well as normalisation of cardiac AMP-activated protein kinase and endothelial nitric oxide synthase activities. Our results indicate that chronic BNP treatment at low dose improves the metabolic profile and prevents the development of myocardial dysfunction in db/db mice.

Congestive Heart Failure and Quality of Life

Our study aimed to assess the quality of life (QoL) of patients with congestive heart failure (CHF) and to correlate the different aspects of QoL with relevant socio-demographic variables, CHF severity, somatic comorbidities, other clinical variables and depressive symptomatology. In a cross-sectional study design, a community sample of 103 adult patients with CHF (mean age 68 years, 73 % male) was recruited from an outpatient cardiology practice. CHF severity was assessed with physician ratings of the New York Heart Association (NYHA) functional class and measurement of brain natriuretic peptide (BNP) levels. The psychometric evaluation of quality of life was made using the Medical Outcomes Study Short Form-36 (SF-36) and the Kansas City Cardiomyopathy Questionnaire (KCCQ). The Beck Depression Inventory Second Edition (BDI-II) assessed depressive symptoms. Using multiple linear regression, predictors of poorer QoL included being a female, being older, living alone, NYHA functional class ≥ II, higher levels of BNP comorbidity (such as renal insufficiency and cerebrovascular disease), fluid retention, depressive symptomatology (assessed by BDI-II) and treatment with anti-dyslipidemics, diuretics and β-blockers. Among these correlates, psychological distress was the most strongly related to QoL. Also, functional status measured by NYHA demonstrated a high impact on QoL. Our findings suggest the need to address such factors in developing effective care to improve psychological and functional status in order to enhance QoL in these patients.

Abstract 325: Brain Natriuretic Peptide During Coronary Intervention Prevents Endothelial Dysfunction Post PCI via NP-cGMP Activation

Background: Contrast media (CM) administrated during percutaneous coronary intervention (PCI) is associated with endothelial dysfunction (ED) and systemic vascular injury. Brain natriuretic peptide (BNP) administration 24 hours post PCI decreases ED. Aims: To evaluate 1.The ability of human BNP (hBNP) infusion during PCI, to prevent ED in acute coronary syndrome's (ACS) patients post the PCI. 2. The effect of CM on human coronary microvascular endothelial cells (HCMEC).3. Explain ED by invitro study. Methods and results (in vivo): Non-ST elevation ACS patients who underwent PCI (111) were randomized into 2 groups: an hBNP group who received hBNP infusion during the procedure (n=44), and control group who received nitroglycerin (n=67). Flow mediated dilatation (FMD) (by ≥2.5%), BNP, corin, serum creatinine (sCr) and estimate Glomerular Filtration Rate (eGFR), before and 24 hr after operative were recorded, starting with the same baseline. The post PCI FMD and eGFR were significantly reduced in the control group (p=0.05, 0.002) but not in the hBNP group (p=0.16, 0.4). BNP, corin and sCr increased significantly in the control group (p=0.001, 0.003, 0.0002 respectively) but not in hBNP group (p=0.09, 0.07, 0.18). Methods and results (in vitro): HCMEC were treated with CM (10%) in the presence and absence of BNP. eNOS, corin and cGMP levels were measured by ELISA and the results were compared to untreated cells. In both treatments eNOS was significantly reduced (p=0.001) and corin was significantly increased (p=0.002). cGMP was not affected by CM treatment (p=0.278), but was increased significantly (p=0.001) by hBNP combination. cGMP immuno-flourescence staining of HCMEC showed distorted cellular cGMP appearance by CM treatment, that was corrected in the combination with hBNP with accentuated subsarcolemmal staining. Conclusions: CM reduces eNOS level in HCMEC. Therefore, reduced in NO-cGMP pathway's products, probably is the mechanism that induces ED in-vivo. BNP treatment reduces FMD diminution and kidney injury post PCI. A compensatory rise in corin that increases BNP as well as the hBNP administration, invivo and invitro, maintains cytosolic cGMP via NP-cGMP pathway, and compensates for NO-cGMP loss, (reduced sGC) and thus prevents ED.

Direct actions of Brain Natriuretic Peptide (BNP) on brown adipose tissue include stimulation of Monocyte Chemoattractant Protein-1 (MCP-1), angiotensin II, and leptin

Brain natriuretic peptide (BNP) regulates salt/water balance and vascular tone. Blood levels of this hormone are clinically used as a sensitive marker for cardiac failure, a major complication of the metabolic syndrome. Adipose tissue plays a key role in the pathogenesis of the metabolic syndrome. Brown adipose tissue has been implicated in the development of insulin resistance and obesity in humans and represents a potential therapeutic target tissue. We investigated direct effects of BNP on thermogenesis, differentiation, insulin sensitivity, and endocrine activity in SV40T-immortalized brown adipocytes. Thermogenic function and adipocyte differentiation were unchanged by BNP treatment as measured by UCP-1 mRNA as well as protein expression and Oil Red O staining, respectively. Furthermore, treatment of differentiated cells with BNP (1µM) from 1 to 24h did not change the insulin-induced glucose-uptake. Consistent with these findings, phosphorylation of signaling molecules mediating insulin's metabolic effects such as Akt, p70S6 or pGSK3 was not significantly altered by acute BNP treatment. However, BNP treatment from 1 to 40 minutes time- and dose-dependently resulted in activation of MAP kinase by maximally 400% after 5 minutes (p<0.01). Furthermore, expression of inflammatory and vasoregulatory adipokines was altered. Thus, monocyte chemoattractant protein-1 (MCP-1) was increased by 60% after 2h of BNP treatment (100 nM, p<0.05). BNP also increased mRNA expression of angiotensin II by 80% and leptin by 40% (p<0.05 and <0.01, respectively). In contrast, adiponectin mRNA levels remained unchanged. Taken together, our data suggest selective direct effects of BNP on the endocrine activity of adipose tissue. These direct actions include the stimulation of inflammatory adipokines such as MCP-1 which is involved in the development of insulin resistance. Thus, this may have implications for the pathogenesis of the metabolic syndrome and its associated cardiovascular complications.