Atrial Natriuretic Peptide Levels Research Articles

Hydrogen (H2) Inhibits Isoproterenol-Induced Cardiac Hypertrophy via Antioxidative Pathways.

Background and Purpose: Hydrogen (H2) has been shown to have a strong antioxidant effect on preventing oxidative stress-related diseases. The goal of the present study is to determine the pharmacodynamics of H2 in a model of isoproterenol (ISO)-induced cardiac hypertrophy.Methods: Mice (C57BL/6J; 8–10 weeks of age) were randomly assigned to four groups: Control group (n = 10), ISO group (n = 12), ISO plus H2 group (n = 12), and H2 group (n = 12). Mice received H2 (1 ml/100g/day, intraperitoneal injection) for 7 days before ISO (0.5 mg/100g/day, subcutaneous injection) infusion, and then received ISO with or without H2 for another 7 days. Then, cardiac function was evaluated by echocardiography. Cardiac hypertrophy was reflected by heart weight/body weight, gross morphology of hearts, and heart sections stained with hematoxylin and eosin, and relative atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) mRNA levels. Cardiac reactive oxygen species (ROS), 3-nitrotyrosine and p67 (phox) levels were analyzed by dihydroethidium staining, immunohistochemistry and Western blotting, respectively. For in vitro study, H9c2 cardiomyocytes were pretreated with H2-rich medium for 30 min, and then treated with ISO (10 μM) for the indicated time. The medium and ISO were re-changed every 24 h. Cardiomyocyte surface areas, relative ANP and BNP mRNA levels, the expression of 3-nitrotyrosine, and the dissipation of mitochondrial membrane potential (MMP) were examined. Moreover, the expression of extracellular signal-regulated kinase1/2 (ERK1/2), p-ERK1/2, p38, p-p38, c-Jun NH2-terminal kinase (JNK), and p-JNK were measured by Western blotting both in vivo and in vitro.Results: Intraperitoneal injection of H2 prevented cardiac hypertrophy and improved cardiac function in ISO-infused mice. H2-rich medium blocked ISO-mediated cardiomyocytes hypertrophy in vitro. H2 blocked the excessive expression of NADPH oxidase and the accumulation of ROS, attenuated the decrease of MMP, and inhibited ROS-sensitive ERK1/2, p38, and JNK signaling pathways.Conclusion: H2 inhibits ISO-induced cardiac/cardiomyocytes hypertrophy both in vivo and in vitro, and improves the impaired left ventricular function. H2 exerts its protective effects partially through blocking ROS-sensitive ERK1/2, p38, and JNK signaling pathways.

(-)-Epicatechin induces physiological cardiac growth by activation of the PI3K/Akt pathway in mice.

The flavanol (-)-epicatechin (Epi) has cardioprotective effects and improves physical capacity in normal mice. In addition, Epi increases nitric oxide (NO) production by activation of both PI3K/Akt or Ca2+ /CaMI/CaMKII (where Akt is protein kinase B; PI3K is phosphoinositide 3-kinase; CaMI is calmodulin; CaMKII is Ca2+ /calmodulin-dependent protein kinase II) signaling pathways, which have been associated with physiological and pathological cardiac hypertrophy, respectively. Notwithstanding all this information, few studies have been carried out that aimed to determine the potential beneficial effects that Epi may have in normal heart. Mice were treated by oral gavage with the flavanol Epi. The treatment induced a significant increase in heart weight, size of the free walls, and size of the cardiac fibers. Also, no evidence of cardiac fibrosis was revealed. Furthermore, the phosphorylation level of PI3K/Akt/mTOR/p70S6K (where mTOR is mammalian target of rapamycin; p70S6K is ribosomal protein S6 kinase beta-1) proteins was significantly higher in the heart of Epi-treated animals. In contrast, a significantly decreased level of pathological cardiac hypertrophy markers atrial natriuretic peptide and brain natriuretic peptide was observed along with no modification in the level of β myosin heavy chain beta, calmodulin, and Ca2+ /calmodulin-dependent protein kinase II proteins. Hemodynamic parameters indicated an improvement in mechanical heart performance after Epi treatment. Interestingly, morphometric parameters were similar between treated and untreated mice after 4 wk without treatment. These findings indicate that Epi treatment induced physiological cardiac growth in healthy mice by activation of the PI3K/Akt pathway.

PP.14.05] CHANGES IN NATRIURETIC PEPTIDES LEVELS IN PATIENTS WITH HYPERTENSION AND PERSISTENT ATRIAL FIBRILLATION

Objective: To evaluate the changes in atrial natriuretic peptide (NT-proANP) and brain natriuretic peptide (NT-proBNP) levels in patients with hypertension and persistent atrial fibrillation (AF) treated with propafenone. Design and method: The study included 60 patients with hypertension and persistent AF aged 46 to 67 years (mean age 61.1 ± 8.8 years). After the sinus rhythm restoration, patients were divided into 2 groups: the first group (30 patients) was treated with propafenone 450 mg for sinus rhythm maintenance during the next 6 months; the second group (30 patients) received bisoprolol for rate control. All patients were comparable in relation to age, sex, duration of hypertension and AF paroxysms. Natriuretic peptides levels were measured within the first 24 hours after sinus rhythm restoration and after 6 months of treatment. Results: On the first day after sinus rhythm restoration elevation of NT-proBNP and NT-proANP was found, there was no significant difference between the groups. NT-proBNP levels in the first and second groups were 160.5 ± 15.2 pg/ml and 158.2 ± 8.6 pg/ml, respectively; NT-proANP levels in the first and second groups were 15.3 ± 6.4 nmol /l and 16.7 ± 8.2 nmol /l, respectively. After 6 months of sinus rhythm maintenance plasma concentration of NT-proBNP and NT-proANP reduced significantly from 160.5 ± 15.2 pg/ml to 130.1 ± 12.2 pg/ml and from 15.3 ± 6.4 nmol/l to 11.5 ± 5.3 nmol/l, respectively, in the first group (p < 0.05). There was no significant difference in NT-proBNP and NT-proANP levels after 6-month treatment period with bisoprolol. Conclusions: NT-proANP and NT-proBNP levels in patients with hypertension and persistent AF were significantly reduced after 6 months of sinus rhythm maintenance with propafenone.

High recurrence of atrial fibrillation in patients with high tissue atrial natriuretic peptide and amyloid levels after concomitant maze and mitral valve surgery

BackgroundHemodynamic burden is thought to play a role in valvular atrial fibrillation (AF), but the detailed pathophysiology is unclear. We hypothesized that atrial natriuretic peptide (ANP) tissue levels and amyloid deposits in the left atrial appendage (LAA) were associated with the pre-operative hemodynamic status and post-operative rhythm outcome in patients undergoing a concomitant mitral valve and maze surgery. MethodsWe quantified the fibrosis, atrial amyloid deposits, ANP tissue levels, and multiple biomarker proteins (Western blot) in LAA tissues taken from 26 patients (53.8% male, 58.4±9.7 years) who underwent concomitant maze and mitral valve surgery. The histologic and biochemical results were compared with the pre-operative pulmonary artery pressure (PAP) and post-operative rhythm outcome. ResultsThe ANP tissue level was positively correlated with the atrial amyloid deposit areas (R=0.880, p<0.001), but not with the degree of fibrosis. The pre-operative systolic PAP negatively correlated with both the ANP tissue expression level (R=−0.467, p=0.019) and atrial amyloid deposit area (R=−0.589, p=0.008). The angiotensin II tissue expression level was significantly higher in tissues without ANP expression than in those with expression (p=0.003). AF recurrence after the maze operation was significantly lower in patients without than in those with ANP expression (log rank p=0.031, HR 3.779, 95% CI 1.163–12.277, p=0.027). ConclusionsA lower ANP atrial tissue expression and amyloid deposits were correlated with a high pre-operative hemodynamic loading, and those patients had a paradoxically lower AF recurrence after relief of the hemodynamic burden by concomitant maze and mitral valve surgery.

Abstract 292: The Role of the ATF6 Branch of the ER Stress Response in the Endocrine Heart

Rationale: Atrial natriuretic peptide (ANP) is stored in the heart in large dense core granules of atrial myocytes as a biologically inactive precursor, pro-ANP. Hemodynamic stress and atrial stretch stimulate coordinate secretion and proteolytic cleavage of pro-ANP to its bioactive form, ANP, which promotes renal salt excretion and vasodilation, which, together contribute to decreasing blood pressure. While the ATF6 branch of the ER stress response has been studied in ventricular tissue mouse models of myocardial ischemia and pathological hypertrophy, roles for ATF6 and ER stress on the endocrine function of atrial myocytes have not been studied. Objective/Methods: To address this gap in our knowledge, we knocked down ATF6 in primary cultured neonatal rat atrial myocytes (NRAMs) using a chemical inhibitor of the proteolytic cleavage site enabling ATF6 activation and siRNA and measured ANP expression and secretion basally and in response to alpha- adrenergic agonist stimulation using phenylephrine. We also compared the ANP secretion from wild- type mice and ATF6 knockout mice in an ex vivo Langendorff model of the isolated perfused heart. Results: ATF6 knockdown in NRAMs significantly impaired basal and phenylephrine-stimulated ANP secretion. ATF6 knockout mice displayed lower levels of ANP in atrial tissue at baseline as well as after phenylephrine treatment. Similarly, in the ex vivo isolated perfused heart model, less ANP was detected in effluent of ATF6 knockout hearts compared to wild-type hearts. Conclusions: The ATF6 branch of the ER stress response is necessary for efficient co-secretional processing of pro-ANP to ANP and for agonist-stimulated ANP secretion from atrial myocytes. As ANP is secreted in a regulated manner in response to a stimulus and pro-ANP is synthesized and packaged through the classical secretory pathway, we posit that ATF6 is required for adequate expression, folding, trafficking, processing and secretion of biologically active ANP from the endocrine heart.

CYP2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPKα2 and enhancing nuclear translocation of Akt1.

SummaryCytochrome P450 epoyxgenase 2J2 and epoxyeicosatrienoic acids (EETs) are known to protect against cardiac hypertrophy and heart failure, which involve the activation of 5′‐AMP‐activated protein kinase (AMPK) and Akt. Although the functional roles of AMPK and Akt are well established, the significance of cross talk between them in the development of cardiac hypertrophy and antihypertrophy of CYP2J2 and EETs remains unclear. We investigated whether CYP2J2 and its metabolites EETs protected against cardiac hypertrophy by activating AMPKα2 and Akt1. Moreover, we tested whether EETs enhanced cross talk between AMPKα2 and phosphorylated Akt1 (p‐Akt1), and stimulated nuclear translocation of p‐Akt1, to exert their antihypertrophic effects. AMPKα2−/− mice that overexpressed CYP2J2 in heart were treated with Ang II for 2 weeks. Interestingly, overexpression of CYP2J2 suppressed cardiac hypertrophy and increased levels of atrial natriuretic peptide (ANP) in the heart tissue and plasma of wild‐type mice but not AMPKα2−/− mice. The CYP2J2 metabolites, 11,12‐EET, activated AMPKα2 to induce nuclear translocation of p‐Akt1 selectively, which increased the production of ANP and therefore inhibited the development of cardiac hypertrophy. Furthermore, by co‐immunoprecipitation analysis, we found that AMPKα2β2γ1 and p‐Akt1 interact through the direct binding of the AMPKγ1 subunit to the Akt1 protein kinase domain. This interaction was enhanced by 11,12‐EET. Our studies reveal a novel mechanism in which CYP2J2 and EETs enhanced Akt1 nuclear translocation through interaction with AMPKα2β2γ1 and protect against cardiac hypertrophy and suggest that overexpression of CYP2J2 might have clinical potential to suppress cardiac hypertrophy and heart failure.

Association of pre-ablation level of potential blood markers with atrial fibrillation recurrence after catheter ablation: a meta-analysis.

The meta-analysis was aimed to search for candidate blood markers whose pre-ablation level was associated with atrial fibrillation (AF) recurrence after radiofrequency catheter ablation (RFCA). A systematic literature search of PubMed, EMBASE, Springer Link, Web of Science, Wiley-Cochrane library, and supplemented with Google scholar search engine was performed. Thirty-six studies covering 11 blood markers were qualified for this meta-analysis. Compared with the nonrecurrence group, the recurrence group had increased pre-ablation level of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-pro-BNP), interleukin-6 (IL-6), C-reactive protein, low density lipoprotein (LDL), and tissue inhibitor of metal loproteinase-2 (TIMP-2) [standardized mean difference (95% confidence interval): 0.37 (0.13-0.61), 0.77 (0.40-1.14), 1.25 (0.64-1.87), 0.37 (0.21-0.52), 0.35 (0.10-0.60), 0.24 (0.07-0.42), 0.17 (0.00-0.34), respectively], while no statistical difference of pre-ablation level of white blood cell, total cholesterol, triglyceride, and transforming growth factor-β1 was found. Subgroup analysis demonstrated that ANP was associated with AF recurrence in participants who had no concomitant structural heart diseases (SHD); however, not in participants who had SHD, C-reactive protein was associated with AF recurrence in Asian studies, whereas not in European studies. Increased pre-ablation level of ANP, BNP, NT-pro-BNP, IL-6, C-reactive protein, LDL, and TIMP-2 was associated with greater risk of AF recurrence after RFCA.

MiR-155 functions downstream of angiotensin II receptor subtype 1 and calcineurin to regulate cardiac hypertrophy.

Cardiac hypertrophy is characterized by maladaptive tissue remodeling that may lead to heart failure or sudden death. MicroRNAs (miRs) are negative regulators of angiotensin II and the angiotensin II receptor subtype 1 (AGTR1), which are two components involved in cardiac hypertrophy. In the present study, the interaction between angiotensin II receptor subtype 1 (AGTR1) signaling and miR-155 was investigated. Rat H9C2 (2-1) cardiomyocytes were transfected with miR-155 analogues or inhibitors, then stimulated with angiotensin II to induce cardiac hypertrophy. miR-155 expression was revealed to be altered following transfection with chemically-modified miR-155 analogues and inhibitors in rat cardiomyocytes. In cell cardiac hypertrophy models, the cell surface area, AGTR1, atrial natriuretic peptide and myosin heavy chain-β mRNA expression levels were revealed to be lower in cells stimulated with miR-155 analogue-transfected cells treated with angiotensin II compared with cells stimulated with angiotensin alone (P<0.05), as determined using reverse transcription-polymerase chain reaction (PCR), quantitative PCR and western blot analyses. Furthermore, calcineurin mRNA and protein, intracellular free calcium and nuclear factor of activated T-cells-4 proteins were downregulated in miR-155 analogue-transfected cells treated with angiotensin II, as compared with cells stimulated with angiotensin II alone (P<0.05). In conclusion, the current study indicates that miR-155 may improve cardiac hypertrophy by downregulating AGTR1 and suppressing the calcium signaling pathways activated by AGTR1.

Serum levels of ANP signaling in different degree of allergic asthmatics and its role in the pathogenesis of allergic asthma

To investigate the relationship between the severity of allergic asthma and the levels of atrial natriuretic peptide (ANP), and to analyze the potential role of ANP signaling in the pathogenesis of asthma. We recruited 96 subjects, including 23 healthy volunteers, 25 stable allergic asthmatics, 21 mild allergic asthmatics and 27 moderate allergic asthmatics, from the Affiliated Hospital of Guilin Medical University. ANP, IFN-γ and IL-4 levels in serum were detected by enzyme-linked immunosorbent assay (ELISA), and the mRNA and protein expressions of natriuretic peptide receptor A (NPRA), transcription factor T-bet and GATA3 were measured by RT-PCR and Western blot. The levels of ANP in serum and the expressions of NPRA mRNA and protein in the peripheral blood mononuclear cell (PBMC) from the mild asthma group or the moderate group were elevated compared with those in the stable asthma group or the mild group, respectively (P<0.05). Consistently, expressions of GATA3 and levels of IL-4 showed the same tendency (P<0.05). In addition, levels of ANP in serum were positively correlated with the severity of asthma, whereas negatively correlated with the ratio of T-bet/GATA3 and IFN-γ/IL-4 (r=-0.85, P<0.05; r=-0.88, P<0.05, respectively). Levels of ANP signaling in serum were significantly increased with the severity of allergic asthma, suggesting a close relation with the pathogenesis of asthma; ANP signaling may play a role in the pathogenesis of allergic asthma through inducing the Th2-type immune response.

Novel MicroRNA Regulators of Atrial Natriuretic Peptide Production.

Atrial natriuretic peptide (ANP) has a central role in regulating blood pressure in humans. Recently, microRNA 425 (miR-425) was found to regulate ANP production by binding to the mRNA of NPPA, the gene encoding ANP. mRNAs typically contain multiple predicted microRNA (miRNA)-binding sites, and binding of different miRNAs may independently or coordinately regulate the expression of any given mRNA. We used a multifaceted screening strategy that integrates bioinformatics, next-generation sequencing data, human genetic association data, and cellular models to identify additional functional NPPA-targeting miRNAs. Two novel miRNAs, miR-155 and miR-105, were found to modulate ANP production in human cardiomyocytes and target genetic variants whose minor alleles are associated with higher human plasma ANP levels. Both miR-155 and miR-105 repressed NPPA mRNA in an allele-specific manner, with the minor allele of each respective variant conferring resistance to the miRNA either by disruption of miRNA base pairing or by creation of wobble base pairing. Moreover, miR-155 enhanced the repressive effects of miR-425 on ANP production in human cardiomyocytes. Our study combines computational, genomic, and cellular tools to identify novel miRNA regulators of ANP production that could be targeted to raise ANP levels, which may have applications for the treatment of hypertension or heart failure.

Novel Chemiluminescent Enzyme Immunoassays for Individual Quantification of 3 Endogenous Molecular Forms of Atrial Natriuretic Peptide in Human Plasma.

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are cardiac peptide hormones with pivotal roles in maintaining cardiovascular homeostasis. BNP and its precursor fragment are accepted as gold standard markers for heart failure (HF). Human ANP is present in the atria of the heart and plasma as 3 endogenous molecular forms designated α-ANP, β-ANP, and proANP. A previous study indicated that the ratios of these 3 ANP forms are altered in the plasma of HF patients. The purpose of our study was to establish immunoassays for quantifying the individual ANP forms to collect clinical information. We developed 3 plate-based chemiluminescent enzyme immunoassays (CLEIAs) for measuring total ANP (i.e., sum of α-ANP, β-ANP, and proANP), β-ANP, and proANP levels. To minimize background signals, we added single-step PEGylation targeting the immobilized antibody in the conventional plate-based sandwich CLEIA procedure. CLEIAs with PEGylation showed sensitivity, specificity, reproducibility, and accuracy satisfying clinical requirements. Two of the CLEIAs enabled direct measurement in plasma samples. During treatments, acute decompensated HF patients exhibited marked decreases in plasma β-ANP levels but moderate decreases in plasma proANP level. The plasma ratios of α-ANP/total ANP and proANP/total ANP in acute decompensated HF patients were maintained, whereas the β-ANP/total ANP ratio was significantly decreased at discharge. The combination of the 3 CLEIAs enabled accurate quantification of α-ANP, β-ANP, and proANP, even in plasma samples, and indicated the potential of β-ANP and proANP as circulating biomarkers for HF, with different characteristics from that of BNP.

Evaluation of Serum Levels of N-terminal Pro Brain Natriuretic Peptide and Atrial Natriuretic Peptide in Neonates with Respiratory Distress

Background: Acute respiratory distress (ARD) is a critical respiratory failure due to lung injury of neonates leading to the clinical appearance of poor lung compliance. The aimed of the study was to evaluate the diagnostic values in differentiating respiratory from heart diseases with using of N-terminal pro brain natriuretic peptide (NT-pro BNP) and Atrial natriuretic peptide(ANP) in neonates. Material and Methods: Ninety neonates randomly collected from those who hospitalized in the neonate ward of the Ali Ebne abitalib Hospital, Zahedan, Iran .After taking blood samples ANP and NT pro Brian Natriuretic peptide using ELISA kit were measured. The separated serum was kept in -20 °C until BNP measurement. 250 μl of the patients’ serum was isolated to assess pro BNP level using ELISA kit (USA). Data were analyzed using SPSS- 20 with considering of P< 0.05. Results: NT pro-BNP level had the highest in cardiac patients and followed by respiratory. The level of NT pro-BNP for control neonates had the lowest. These levels had significant variation (P<0.05). The level of ANP had the lowest for the cardiac patients. ANP level had the lowest for the acyanotic. NT pro-BNP had the highest concentration in acyanotic patients and and had the second highest concentration in cyanotic. Respiratory diseases ranked in the third levels in concentration of pro-BNP. The level of NT pro-BNP had the lowest for controls. The analysis showed a significant difference in the level of NT pro-BNP (P<0.05). Conclusion: Many studies revealed that NT pro-BNP cannot be used as a tool for differentiation between cardiac and respiratory as a cause of respiratory distress during neonate, but the results of the present study showed that it would be good biomarker.

Sodium-glucose co-transporter-2 inhibitors suppress atrial natriuretic peptide secretion in patients with newly diagnosed Type 2 diabetes.

To observe changes in atrial natriuretic peptide levels after treatment with sodium-glucose co-transporter-2 inhibitors in patients with newly diagnosed type 2 diabetes. A total of 28 patients with newly diagnosed Type 2 diabetes and HbA1c levels of 58 -91 mmol/mol (7.5-10.5%) were randomly selected to receive sodium-glucose co-transporter-2 inhibitor treatment (n = 18) or placebo (n = 10) for 24 weeks. We analysed atrial natriuretic peptide concentrations, using an enzyme-linked immunosorbent assay. In addition, sodium and HbA1c levels were measured at baseline, 12 weeks and 24 weeks and blood lipid levels and insulin sensitivities at baseline and 24 weeks. Compared with patients treated with placebo, patients who received sodium-glucose co-transporter-2 inhibitor treatment exhibited lower atrial natriuretic peptide levels (36.74 vs 56.90 pg/ml in the placebo group; P < 0.05) and higher sodium levels (144.3 vs 141.4 mmol/l in the placebo group; P < 0.01) at 24 weeks, after adjusting for baseline values. HbA1c levels were lower after sodium-glucose co-transporter-2 inhibitor treatment compared with placebo (51 vs 60 mmol/mol; P < 0.01). No correlation was found between atrial natriuretic peptide and HbA1c levels. Homeostatic model assessment of β-cell function values and lipid profiles were generally similar after 24 weeks of treatment with placebo or sodium-glucose co-transporter-2 inhibitor. This study shows the ability of sodium-glucose co-transporter-2 inhibitors to lower atrial natriuretic peptide levels and improve glycaemic control, which may benefit the cardiovascular system.

Increased extracellular water measured by bioimpedance and by increased serum levels of atrial natriuretic peptide in RA patients-signs of volume overload.

The aim of the study is to investigate water compartments in patients with rheumatoid arthritis (RA). Acute inflammatory episodes such as infection stimulate water retention, chiefly implemented by the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. This is an important compensatory mechanism due to expected water loss (sweating etc.). Since SNS and HPA axis are activated in RA, inflammation might be accompanied by water retention. Using bioimpedance analysis, body composition was investigated in 429 controls and 156 treatment-naïve RA patients between January 2008 and December 2014. A group of 34 RA patients was tested before and after 10days of intensified therapy. Levels of pro-atrial natriuretic peptide (proANP) and expression of atrial natriuretic peptide in synovial tissue were investigated in 15 controls and 14 RA patients. Extracellular water was higher in RA patients than controls (mean ± SEM: 49.5 ± 0.3 vs. 36.7 ± 0.1, % of total body water, p < 0.0001). Plasma levels of proANP were higher in RA than controls. RA patients expressed ANP in synovial tissue, but synovial fluid levels and synovial tissue superfusate levels were much lower than plasma levels indicating systemic origin. Systolic/diastolic blood pressure was higher in RA patients than controls. Extracellular water levels did not change in RA patients despite 10days of intensified treatment. This study demonstrates signs of intravascular overload in RA patients. Short-term intensification of anti-inflammatory therapy induced no change of a longer-lasting imprinting of water retention indicating the requirement of additional treatment. The study can direct attention to the area of volume overload.

Transient silencing of Npr3 gene expression improved the circulatory levels of atrial natriuretic peptides and attenuated β-adrenoceptor activation- induced cardiac hypertrophic growth in experimental rats

Natriuretic peptide receptor-C (NPR-C) is considered as a clearance receptor that maintains the circulatory levels of natriuretic peptides. It has been suggested that augmented expression of NPR-C as a cause for the diminished anti-hypertrophic action of natriuretic peptides in the failing heart. Hence, we sought to determine the level of Npr3 gene (coding for NPR-C) expression in the Isoproterenol (ISO) treated Wistar rats. In addition, we studied the effect of Npr3 gene silencing on the hypertrophic growth. A significant increase in heart weight-to-body weight ratio (HW/BW-24%,P<0.01), an indicator of cardiac hypertrophic growth was observed in the ISO (10mg/kg BW/day,i.p for 7 days) treated rats. As expected, the cardiac NPR-C protein expression was significantly increased by 4 fold as compared to control rats. In parallel, the circulatory atrial natriuretic peptide (ANP) level was significantly decreased (2 fold) in ISO treated rats. Upon treatment with siRNA-Npr3, a significant decrease in the cardiac NPR-C protein expression (70%,P<0.01), HW/BW ratio (70%,P<0.01) and hypertrophic marker genes (α-Sk, β-MHC, c-fos, P<0.01, respectively) mRNA expression were observed. Interestingly, the circulatory ANP level was increased by 1.5 fold in the siRNA-Npr3 treated rats as compared to ISO treated rats. Moreover, the cardiac collagen content, matrixmetalloprotinases-2 (MMP-2) and enzymatic antioxidant status (P<0.01, respectively) were found to be restored back to near normal upon siRNA-Npr3 treatment. Taken together, the results of this study indicates that specific down-regulation of Npr3 gene improves the circulatory levels of ANP and antioxidant system and there by attenuates the β-adrenoceptor over-activation mediated cardiac hypertrophic growth in experimental rats.

Are endogenous cardenolides controlled by atrial natriuretic peptide

Endogenous cardenolides are digoxin-like substances and ouabain-like substances that have been implicated in the pathogenesis of hypertension and mood disorders in clinical and pre-clinical studies. Regulatory signals for endogenous cardenolides are still unknown. These endogenous compounds are believed to be produced by the adrenal gland in the periphery and the hypothalamus in the central nervous system, and constitute part of an hormonal axis that may regulate the catalytic activity of the α subunit of Na+/K+-ATPase. A review of literature suggests that there is great overlap in physiological environments that are associated with either elevations or reductions in the levels of atrial natriuretic peptide (ANP) and endogenous cardenolides. This suggests that these two factors may share a common regulatory signal or perhaps that ANP may be involved in the regulation of endogenous cardenolides.

Adiponectin Upregulates MiR-133a in Cardiac Hypertrophy through AMPK Activation and Reduced ERK1/2 Phosphorylation.

Adiponectin and miR-133a are key regulators in cardiac hypertrophy. However, whether APN has a potential effect on miR-133a remains unclear. In this study, we aimed to investigate whether APN could regulate miR-133a expression in Angiotensin II (Ang II) induced cardiac hypertrophy in vivo and in vitro. Lentiviral-mediated adiponectin treatment attenuated cardiac hypertrophy induced by Ang II infusion in male wistar rats as determined by reduced cell surface area and mRNA levels of atrial natriuretic peptide (ANF) and brain natriuretic peptide (BNP), also the reduced left ventricular end-diastolic posterior wall thickness (LVPWd) and end-diastolic interventricular septal thickness (IVSd). Meanwhile, APN elevated miR-133a level which was downregulated by Ang II. To further investigate the underlying molecular mechanisms, we treated neonatal rat ventricular myocytes (NRVMs) with recombinant rat APN before Ang II stimulation. Pretreating cells with recombinant APN promoted AMP-activated protein kinase (AMPK) phosphorylation and inhibited ERK activation. By using the inhibitor of AMPK or a lentiviral vector expressing AMPK short hairpin RNA (shRNA) cancelled the positive effect of APN on miR-133a. The ERK inhibitor PD98059 reversed the downregulation of miR-133a induced by Ang II. These results indicated that the AMPK activation and ERK inhibition were responsible for the positive effect of APN on miR-133a. Furthermore, adiponectin receptor 1 (AdipoR1) mRNA expression was inhibited by Ang II stimulation. The positive effects of APN on AMPK activation and miR-133a, and the inhibitory effect on ERK phosphorylation were inhibited in NRVMs transfected with lentiviral AdipoR1shRNA. In addition, APN depressed the elevated expression of connective tissue growth factor (CTGF), a direct target of miR-133a, through the AMPK pathway. Taken together, our data indicated that APN reversed miR-133a levels through AMPK activation, reduced ERK1/2 phosphorylation in cardiomyocytes stimulated with Ang II, revealing a previously undemonstrated and important link between APN and miR-133a.

Responses of cardiac natriuretic peptides after paroxysmal supraventricular tachycardia: ANP surges faster than BNP and CNP

Atrial natriuretic peptide (ANP) secretion increases after 30 min of paroxysmal supraventricular tachycardia (PSVT). Whether this phenomenon also applies to brain or C-type natriuretic peptides (BNP or CNP) remains unknown. Blood samples of 18 patients (41 ± 11 yr old; 4 men) with symptomatic PSVT and normal left ventricular systolic function (ejection fraction 65 ± 6%) were collected from the coronary sinus (CS) and the femoral artery (FA) before and 30 min after the induction, and 30 min after the termination of PSVT. The results showed that the ANP levels rose steeply after the PSVT and then reduced at 30 min after the termination (baseline vs. post-PSVT vs. posttermination: CS: 34.0 ± 29.6 vs. 74.1 ± 42.3 vs. 46.1 ± 32.9; FA: 5.9 ± 3.24 vs. 28.2 ± 20.7 vs. 10.0 ± 4.6 pg/ml; all P < 0.05). In contrast, compared with ANP, the increases of BNP and CNP in CS after the PSVT were less sharp, but continued to rise after the termination of tachycardia (BNP, 10.2 ± 6.4 vs. 11.3 ± 7.1 vs. 11.8 ± 7.9; CNP, 4.5 ± 1.2 vs. 4.9 ± 1.4 vs. 5.0 ± 1.4 pg/ml; all P < 0.05). The rise of BNP and CNP in FA was similarly less sharp after the PSVT and remained stationary after the termination. PSVT exerted differential effects on cardiac natriuretic peptide levels. ANP increased greater after a 30-min induced PSVT, but dropped faster after termination of PSVT, compared with BNP and CNP.

Exenatide infusion decreases atrial natriuretic peptide levels by reducing cardiac filling pressures in type 2 diabetes patients with decompensated congestive heart failure.

BackgroundThe vascular effects exerted by GLP-1 are mediated by several synergistic mechanisms such as involvement of nitric oxide and natriuresis. Recently, it was demonstrated that atrial natriuretic peptide (ANP) is essential for the glucagon-like peptide-1 (GLP-1)-stimulated vascular smooth muscle relaxation that mediates anti-hypertensive action in rodents. Therefore a GLP-1–ANP axis has been suggested. The aim of this study was to investigate whether this effect can be demonstrated in patients with type 2 diabetes and congestive heart failure.MethodsThe study was a post hoc analysis of a randomized double-blinded, placebo-controlled trial. Twenty male patients with type 2 diabetes and congestive heart failure were randomized to receive a 6-h infusion of exenatide or placebo. Cardiac filling pressures were measured by right heart catheterization, and plasma levels of ANP, N-terminal pro-brain natriuretic peptide, and exenatide were measured at baseline and at the end of the exenatide infusion.ResultsExenatide infusion resulted in a significant decrease of circulating ANP levels compared with placebo, concomitant with a decrease in pulmonary capillary wedge pressure (PCWP), pulmonary artery pressure (PAP) and right arterial pressure (RAP), and increased cardiac output. There was no correlation between plasma ANP levels and exenatide levels. A negative correlation between ANP levels and PCWP, PAP, and RAP, which remained significant after adjustment for plasma exenatide levels, was demonstrated during exenatide infusion.ConclusionsExenatide infusion decreases cardiac filling pressure and ANP levels. The reduction of ANP levels was primarily because of the reduction in cardiac filling pressure, independent of exenatide levels. It seems unlikely that this was mediated via ANP.Trial registration: http://www.isrctn.org/ISRCTN47533126

Pre-Procedural Serum Atrial Natriuretic Peptide Levels Predict Left Atrial Reverse Remodeling After Catheter Ablation in Patients With Atrial Fibrillation.

This study aimed to investigate the role of atrial natriuretic peptide (ANP) levels to predict left atrial (LA) reverse remodeling in atrial fibrillation (AF) patients. Although LA reverse remodeling after radiofrequency catheter ablation (RFCA) for AF was reported to be associated with favorable outcomes and improvement of LA and left ventricular function, the predictor has not been extensively evaluated. This study included 104 consecutive patients who underwent RFCA for AF. All patients underwent multidetector computed tomography examination and laboratory tests, including measurement of ANP, plasma B-type natriuretic peptide (BNP), and high-sensitivity C-reactive protein (hs-CRP) levels before and 6 months after RFCA. The study population was divided according to the extent of the decrease in the LA volume index at follow-up; responders were defined as patients who exhibited a≥15% decrease in the LA volume index. At follow-up, 49 patients (47%) were classified as responders. Pre-procedural serum ANP and BNP levels were significantly higher in the responders than in the nonresponders (both p< 0.01). In the responders, a significant decrease was observed in the log ANP, log BNP, and log hs-CRP levels from baseline to follow-up (all p< 0.01). Multivariate linear regression analysis revealed that log ANP levels before RFCA and maintenance of sinus rhythm during follow-up were independent predictors of LA reverse remodeling (both p< 0.01). In this study, 47% of the patients exhibited LA reverse remodeling after RFCA for AF, with a concomitant improvement in serum ANP, BNP, and hs-CRP levels. The pre-procedural ANP level and maintenance of sinus rhythm were independently associated with LA reverse remodeling.