Cardiac Atrial Natriuretic Peptide Research Articles

Evaluation of some nonroutine cardiac biomarkers among adults and children with beta-thalassemia major.

Cardiac injury caused by iron overload is the leading cause of mortality and morbidity in patients with beta-thalassemia, owing to frequent blood transfusion, increased iron overload, and blood hemolysis. This research aimed to assess several novel cardiac biomarkers in the blood samples of children and adult patients with beta-thalassemia major (βTM), along with their respective control groups. These biomarkers included endothelin 1 (ET-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), atrial natriuretic peptide (ANP), growth differentiation factor-15 (GDF-15), and renalase (RNLS). This case-control study was done on 46 patients with βTM (23 children <18 years, and 23 adults ≥18 years) from the Genetic Hematology Center in Thi-Qar province, Iraq, and 42 comparable controls in 2 groups (21 for each group) in the period from February to April 2023. Levels of ET-1, NT-proBNP, ANP, GDF-15, RNLS, and ferritin were higher in the children and adults with βTM than in the control subjects. Elevations of the novel cardiac biomarkers ET-1, NT-proBNP, ANP, GDF-15, and RNLS in the sera of children and adult patients with βTM when compared with comparable control subjects confirm that the majority of patients with βTM are at risk of cardiac and cardiovascular complications even when there are no obvious symptoms, especially in children, which gives suitable predictive biomarkers.

G-protein coupled receptor 30 attenuates myocardial hypertrophy by reducing oxidative stress and apoptosis in Ang II-treated mice

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors that mediate the effects of cardiac diseases. GPR30, also named G-protein-coupled estrogen receptor, shows beneficial effect on female patients with heart failure. This research aimed to probe the role and mechanism of GPR30 in myocardial hypertrophy. The model of cardiac hypertrophy was induced by infusion of angiotensin (Ang) II in mice, and was induced by Ang II treatment in neonatal rat cardiomyocyte (NRCM). The mouse model of myocardial hypertrophy was induced by angiotensin (Ang) Ⅱ, and the neonatal rat cardiomyocyte (NRCM) was induced by Ang Ⅱ treatment. GPR30 agonist G1 reduced cardiac hypertrophy induced by Ang II in mice, and reduced cardiac atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) induced by Ang II. Ang Ⅱ treatment of myocardial fibrosis in mice was suppressed after administration of G1. GPR30 deficiency produced the opposite results. Oxidative stress and apoptosis were enhanced in the mice heart induced by Ang II, which were suppressed by G1 administration, but were further exacerbated after GPR30 deficiency. The outcomes demonstrated that GPR30 participated in the regulation of cardiac hypertrophy and fibrosis. Activation of GPR30 ameliorated cardiac hypertrophy and fibrosis by reducing oxidative stress and apoptosis.

Tumstatin (69–88) alleviates heart failure via attenuating oxidative stress in rats with myocardial infarction

BackgroundThis study aimed to elucidate the effects of tumstatin (69–88) on heart failure and the underlying mechanism. Materials and methodsMyocardial infarction (MI) was induced by ligating the left coronary artery in rats to trigger heart failure. ResultsTumstatin (69–88) can reduce cardiac insufficiency in rats with heart failure. The increased cardiac fibrosis in MI rat was attenuated by tumstatin (69–88). Increase of cardiac atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in rats with myocardial infarction, and Ang II-treated NRCMs or H9C2 cells was inhibited by tumstatin (69–88). In the heart of MI rats, and Ang II-treated NRCMs or H9C2 cells, the superoxide anions and NADPH oxidase (Nox) activity rose and the superoxide dismutase (SOD) activity was reduced, which was inhibited by tumstatin (69–88). Diethyldithiocarbamate, an SOD inhibitor, increased the ANP and BNP in NRCMs or H9C2 cells. Tumstatin (69–88) inhibited the Ang II-induced raises of ANP and BNP in NRCMs or H9C2 cells, which was reversed by DETC. ConclusionsThese results indicate that tumstatin (69–88) alleviates cardiac dysfunction of heart failure. Tumstatin (69–88) improves the hypertrophy of cardiomyocytes via attenuation of oxidative stress. Tumstatin (69–88) may be a potential drug for heart failure in the future.

Secretion of Atrial Natriuretic Peptide (ANP), Heart Reconditioning and Remolding in Elite Endurance Trained Athletes

Aim / Objective: The aim of this study was to evaluate the effect of maximal exercise on the level of cardiac remolding and Atrial Natriuretic Peptide (ANP) in elite athletes as compared to sedentary healthy subjects and correlation of ANP with the adaptation of athlete’s heart and cardiac remodeling (if any) Place and Duration of Study: The present study was carried out at the Department of Physiology, Army Medical College, with collaboration of Armed Forces Institute of Cardiology (AFIC) Rawalpindi from June 2003 to May 2004. Methodology: A total number of 44 subjects were included in this study. These comprised of 22 elite endurance athletes and 22 healthy sedentary volunteers as controls. All subjects were examined clinically to rule out the cardiovascular and pulmonary diseases on the basis of medical history, physical examination, and echocardiography. All the selected subjects were examined on a Toshiba Power Vision 6000 echocardiograph for assessing and measuring their LV end-diastolic internal diameter (LVIDd), Diastolic interventricular septal thickness (IVSTd), diastolic posterior wall thickness (PWTd). The left ventricular mass was (LVM) was calculated by using the Devereux formula. They were subject to go for ergometer cycle exercise before breakfast. The Blood samples were drawn before and after exercise to assess the level of ANP in their samples. Results: It was found that LVIDd, IVSTd, PWTd, LVM were higher in athletes as compared to their age, sex and BMI matched controls. The ANP levels in athlete’s plasma were also high in post and pre exercise sample as compared to controls. Conclusion: Systolic blood pressure, Diastolic Blood Pressure and heart rate are lower in endurance elite athletes than matched sedentary controls. The maximal Exercise increases the level of Atrial Natriuretic Peptide (ANP) in elite athletes significantly as compared to sedentary healthy controls. There was a Positive correlations between ANP and LVIDd, IVSTd, PWTd, and LVM while there was negative correlation between ANP and heart rate, ANP and Blood pressure. However, none of correlation was found to be statistically significant. Keywords: Athlete’s Heart, ANP, Cardiac remodeling in athletes, Echocardiography of heart

Treadmill running alleviates adipose tissue browning and lipolysis in rats with heart failure.

This study observed the effects of treadmill running on adipose tissue browning and lipolysis in rats with induced heart failure and elucidated the possible mechanism. Rats underwent abdominal aortic constriction as a model of heart failure. Cardiac function was detected by echocardiography. We detected serum levels of norepinephrine and interleukin 6, cardiac atrial natriuretic peptide and brain natriuretic peptide and marker genes of browning, white adipose tissue (WAT), and lipolysis in adipose tissue. Rats with heart failure showed typical symptoms such as increased heart weight and mRNA levels of atrial natriuretic peptide and brain natriuretic peptide and decreased left ventricular ejection fraction. Exercise partially improved left ventricular diastolic function and significantly decreased atrial natriuretic peptide expression. Rats with heart failure showed significantly reduced body weight and ratios of muscle and fat weight to body weight. Exercise significantly increased body weight and the ratio of muscle weight to body weight. Heart failure stimulated the expression of proliferator-activated receptor-gamma coactivator-1-alpha and uncoupling protein 1 in epididymal WAT, inguinal WAT, and brown adipose tissue but decreased that of adiponectin and leptin in inguinal WAT. Lipolysis, characterized by high adipose triglyceride lipase and hormone-sensitive lipase expression, was activated in all adipose tissues. Exercise reduced browning and lipolysis in adipose tissues. Rats with heart failure had abnormally high levels of serum norepinephrine and interleukin 6, which could be suppressed by exercise. Exercise may improve cardiac cachexia and inhibit the browning and lipolysis of adipose tissue by downregulating sympathetic nervous system activity and inflammation.

Combined deletion of PR-domain containing 16 (Prdm16) in cardiomyocyte and non-cardiomyocyte lineages results in spontaneous early-onset lethality and progressive left ventricular dysfunction in mice

Abstract Introduction PR-domain containing 16 (Prdm16) has an asymmetric expression pattern in the developing cardiovascular system, including ventricular myocardium, endocardium and arterial endothelial and smooth muscle cell (SMC) layers. Heterozygous PRDM16 mutations in humans have been linked with early-onset cardiomyopathy resulting in heart failure. Myocardial PRDM16-deficiency has been suggested as the culprit for this cardiomyopathy, however embryonic Prdm16 deletion in cardiomyocytes or their progenitors in mice only results in symptomatic cardiac defects upon metabolic stress or ageing. This suggests that Prdm16 loss in other cell types has an important co-contribution in the early heart phenotype seen in patients with causal PRDM16 variants. Purpose To investigate the adjuvant role of non-cardiomyocytes to the heart phenotype caused by Prdm16 deficiency, we used a conditional mouse model in which deletion of Prdm16 occurs in all cells expressing an Sm22-driven Cre recombinase which has a combined activity in cardiomyocyte and non-cardiomyocyte lineages in the heart, including SMCs and pericytes. Methods Mice carrying two Prdm16 alleles with a floxed exon 9 (Prdm16fl/fl) were intercrossed with the Sm22-Cre driver line. Offspring of Sm22Cre+; Prdm16fl/fl and Sm22Cre−; Prdm16fl/fl breeding pairs was monitored for Mendelian inheritance and for signs of (progressive) cardiac dysfunction by echocardiography at 5 and 16 weeks of age. Hearts were isolated and analyzed for RNA expression levels of cardiac stress markers Atrial and Brain Natriuretic Peptide (ANP and BNP) via quantitative RT-PCR and histologically for the appearance of fibrosis through Sirius red-staining. Results Genotyping at 5 weeks of age showed a loss of 60.4% of Sm22Cre+; Prdm16fl/fl offspring. Mice surviving at 5 weeks spontaneously developed signs of left ventricular diastolic and systolic dysfunction, the latter shown by a significantly reduced ejection fraction (EF; 37±3% vs. 61±3% in control Sm22Cre−; Prdm16fl/fl littermates). Cardiac expression levels of ANP and BNP were significantly increased (728-fold and 36-fold, respectively) in Sm22Cre+; Prdm16fl/fl mice which also showed perivascular fibrosis compared to control littermates. At 16 weeks of age, this aberrant cardiac phenotype further progressed (EF: 32±3% vs. 57±4%; ANP: 2,541-fold increase; BNP: 129-fold increase) and in addition to perivascular fibrosis, hearts also showed interstitial fibrosis (Sirius red+ area: 17±2% vs. 3.0±0.4% in control littermates). Conclusion Unlike recently reported mice with a Prdm16 deficiency in cardiomyocytes or their (precursor) lineages, mice with a combined loss of Prdm16 in the cardiomyocytes and certain non-cardiomyocyte lineages feature early mortality and (progressive) signs of severe heart failure. Therefore, Prdm16 expressed by non-cardiomyocytes is indispensable for proper cardiac function and its loss in these cell types co-determines the aberrant cardiac phenotype. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fonds voor Wetenschappelijk Onderzoek Strategic Basic Research pre-doctoral fellowship (1S25817N)KU Leuven Research Coordination grant (C14/19/095)

Abstract P140: Mutant Mice Carrying Global Loss Of Npr1 Exhibit Cardiac Fibrosis, Hypertrophy, And Congestive Heart Failure: Implication Of TGF-Beta/SMAD Signaling Pathway

The cardiac hormones, atrial and brain natriuretic peptides (ANP and BNP) bind to natriuretic peptide receptor-A (NPRA), which synthesizes the second messenger cGMP. The objective of this study was to determine the underlying mechanisms that regulate the development of cardiac hypertrophy, fibrosis, and congestive heart failure (CHF) in Npr1 (encoding NPRA) gene-knockout mice. The Npr1 null mutant ( Npr1 -/- , 0-copy), heterozygous ( Npr1 +/- , 1-copy), and wild-type ( Npr1 +/+ , 2-copy) mice were orally administered with transforming growth factor-β1 receptor I (TGF-β1R1) antagonist, GW788388 (2 mg/kg/day) by oral gavage for 28 days. The left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVEDS), posterior wall thickness (PWT), and percent fractional shortening (FS) were analyzed by echocardiography. The heart was isolated and used for the analysis of fibrotic markers using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot methods. The heart weight-to-body weight (HW/BW) ratio, LVEDD, LVEDS and PWT were significantly (p&lt;0.005) increased in Npr1 -/- and Npr1 +/- mice than wild-type Npr1 +/+ mice. The FS was greatly reduced in Npr1 -/- and Npr1 +/- mice compared with Npr1 +/+ mice. The Npr1 -/- null mutant (0-copy) mice showed 52% increase in HW/BW ratio and 6-fold induction of cardiac fibrosis as compared with 2-copy control mice. The cardiac expression of fibrotic markers including collagen-1a (COL-1a; 3.5-fold), connective tissue growth factor (CTGF; 5-fold), α-smooth muscle actin (α-SMA; 4-fold), TGF-β1RI (4-fold), TGF-β1RII (3.5-fold), and SMAD-2/3 proteins (3-to-5 fold) were significantly increased in Npr1 -/- and Npr1 +/- mutant mice compared with age-matched Npr1 +/+ animals. The treatment with TGF-β1R1 antagonist, significantly (p&lt;0.001) prevented the cardiac hypertrophy, fibrosis, CHF, and down-regulated the expression of fibrotic markers and SMAD proteins in mutant mice. The LVEDD, LVEDS, and FS were significantly (p&lt;0.001) improved in the drug treated Npr1 -/- mice. The present results indicate that the cardiac hypertrophy, fibrosis, and CHF in Npr1 mutant mice is regulated through the TGF-β1-mediated SMAD-dependent signaling pathway.

Heart-Microcirculation Connection: Effects of ANP (Atrial Natriuretic Peptide) on Pericytes Participate in the Acute and Chronic Regulation of Arterial Blood Pressure.

Cardiac ANP (atrial natriuretic peptide) moderates arterial blood pressure. The mechanisms mediating its hypotensive effects are complex and involve inhibition of the renin-angiotensin-aldosterone system, increased natriuresis, endothelial permeability, and vasodilatation. The contribution of the direct vasodilating effects of ANP to blood pressure homeostasis is controversial because variable levels of the ANP receptor, GC-A (guanylyl cyclase-A), are expressed among vascular beds. Here, we show that ANP stimulates GC-A/cyclic GMP signaling in cultured microvascular pericytes and thereby the phosphorylation of the regulatory subunit of myosin phosphatase 1 by cGMP-dependent protein kinase I. Moreover, ANP prevents the calcium and contractile responses of pericytes to endothelin-1 as well as microvascular constrictions. In mice with conditional inactivation (knock-out) of GC-A in microcirculatory pericytes, such vasodilating effects of ANP on precapillary arterioles and capillaries were fully abolished. Concordantly, these mice have increased blood pressure despite preserved renal excretory function. Furthermore, acute intravascular volume expansion, which caused release of cardiac ANP, did not affect blood pressure of control mice but provoked hypertensive reactions in pericyte GC-A knock-out littermates. We conclude that GC-A/cGMP-dependent modulation of pericytes and microcirculatory tone contributes to the acute and chronic moderation of arterial blood pressure by ANP. Graphic Abstract A graphic abstract is available for this article.

Atrial Natriuretic Peptide Orchestrates a Coordinated Physiological Response to Fuel Non-shivering Thermogenesis

Atrial natriuretic peptide (ANP) is a cardiac hormone controlling blood volume and pressure in mammals. It is still unclear whether ANP controls cold-induced thermogenesis invivo. Here, we show that acute cold exposure induces cardiac ANP secretion in mice and humans. Genetic inactivation of ANP promotes cold intolerance and suppresses half of cold-induced brown adipose tissue (BAT) activation in mice. While white adipocytes are resistant to ANP-mediated lipolysis at thermoneutral temperature in mice, cold exposure renders white adipocytes fully responsive to ANP to activate lipolysis and a thermogenic program, a physiological response that is dramatically suppressed in ANP null mice. ANP deficiency also blunts liver triglycerides and glycogen metabolism, thus impairing fuel availability for BAT thermogenesis. ANP directly increases mitochondrial uncoupling and thermogenic gene expression in human white and brown adipocytes. Together, these results indicate that ANP is a major physiological trigger of BAT thermogenesis upon cold exposure in mammals.

Effect of insulin on natriuretic peptide gene expression in porcine heart

Gut hormones affect cardiac function and contractility. In this study, we examined whether insulin affects the cardiac atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression and release of proANP-derived peptides in pigs. Anaesthetized pigs were included in an experimental study comparing the effect of hyperinsulinemia in 15 pigs submitted to two different protocols versus 11 control pigs receiving saline infusion. Phosphorylation of Akt on Thr308 was determined by western blotting with a pAkt-Thr308 antibody. The mRNA contents of ANP and BNP were determined with real-time PCR; plasma and cardiac tissue proANP was measured with an immunoluminometric assay targeted against the mid-region of the propeptide and a processing-independent assay. Insulin stimulation increased phosphorylation of Akt Thr308 in both left atrium and left ventricle of porcine hearts (p < 0.005). No change was observed in ANP and BNP mRNA contents in the right or left atrium. BNP mRNA contents in the left ventricle, however, decreased 3-fold (p = 0.02) compared to control animals, whereas the BNP mRNA content in the right ventricle as well as ANP mRNA content in the right and left ventricle did not change following hyperinsulinemia. Moreover, the peptide contents did not change in the four cardiac chambers. Finally, proANP concentrations in plasma did not change during the insulin infusion compared to the control animals. These results suggest that insulin does not have direct effect on atrial natriuretic peptide expression but may have a role in the left ventricle.

Natriuretic Peptides Attenuate Retinal Pathological Neovascularization Via Cyclic Guanosine Monophosphate Signaling in Pericytes and Astrocytes.

In proliferative retinopathies, complications derived from neovascularization cause blindness. During early disease, pericyte's apoptosis contributes to endothelial dysfunction and leakage. Hypoxia then drives VEGF (vascular endothelial growth factor) secretion and pathological neoangiogenesis. Cardiac ANP (atrial natriuretic peptide) contributes to systemic microcirculatory homeostasis. ANP is also formed in the retina, with unclear functions. Here, we characterized whether endogenously formed ANP regulates retinal (neo)angiogenesis. Approach and Results: Retinal vascular development and ischemia-driven neovascularization were studied in mice with global deletion of GC-A (guanylyl cyclase-A), the cGMP (cyclic guanosine monophosphate)-forming ANP receptor. Mice with a floxed GC-A gene were interbred with Tie2-Cre, GFAP-Cre, or PDGF-Rβ-CreERT2 lines to dissect the endothelial, astrocyte versus pericyte-mediated actions of ANP in vivo. In neonates with global GC-A deletion (KO), vascular development was mildly delayed. Moreover, such KO mice showed augmented vascular regression and exacerbated ischemia-driven neovascularization in the model of oxygen-induced retinopathy. Notably, absence of GC-A in endothelial cells did not impact retinal vascular development or pathological neovascularization. In vitro ANP/GC-A/cGMP signaling, via activation of cGMP-dependent protein kinase I, inhibited hypoxia-driven astrocyte's VEGF secretion and TGF-β (transforming growth factor beta)-induced pericyte apoptosis. In neonates lacking ANP/GC-A signaling in astrocytes, vascular development and hyperoxia-driven vascular regression were unaltered; ischemia-induced neovascularization was modestly increased. Remarkably, inactivation of GC-A in pericytes retarded physiological retinal vascularization and markedly enhanced cell apoptosis, vascular regression, and subsequent neovascularization in oxygen-induced retinopathy. Protective pericyte effects of the ANP/GC-A/cGMP pathway counterregulate the initiation and progression of experimental proliferative retinopathy. Our observations indicate augmentation of endogenous pericyte ANP signaling as target for treatment of retinopathies associated with neovascularization.

Differential Regulation of ANP and BNP in Acute Decompensated Heart Failure: Deficiency of ANP

ObjectivesThis study investigated the differential regulation of circulating atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in patients with acute decompensated heart failure (ADHF) and tested the hypothesis that a relative deficiency of ANP exists in a subgroup of patients with ADHF. BackgroundThe endocrine heart releases the cardiac hormones ANP and BNP, which play a key role in cardiovascular (CV), renal, and metabolic homeostasis. In heart failure (HF), both plasma ANP and BNP are increased as a compensatory homeostatic response to myocardial overload. MethodsANP and BNP concentrations were measured in a small group of patients with ADHF (n = 112). To support this study’s goal, a total of 129 healthy subjects were prospectively recruited to establish contemporary normal values for ANP and BNP. Plasma 3′,5′cyclic guanosine monophosphate (cGMP), ejection fraction (EF), and body mass index (BMI) were measured in these subjects. ResultsIn cases of ADHF, 74% of patients showed elevated ANP and BNP. Importantly, 26% of patients were characterized as having normal ANP (21% of this subgroup had normal ANP and elevated BNP). Cyclic GMP was lowest in the ADHF group with normal levels of ANP (p < 0.001), whereas BMI and EF were inversely related to ANP levels (p = 0.003). ConclusionsAmong a subgroup of patients hospitalized with ADHF, the presence of an ANP deficiency is consistent with a differential regulation of ANP and BNP and suggests the existence of a potentially compromised compensatory cardiac endocrine response. These findings have implications for the pathophysiology, diagnostics, and therapeutics of human HF.

Abstract P158: Preeminent Role of the Cardiorenal Axis in the Antihypertensive Response to an Arteriovenous Fistula: An In Silico Analysis

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated in clinical trials for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to: 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After simulating a small fistula there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 weeks BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Further, when chronic resetting of atrial mechanoreceptors was prevented during the fistula RSNA decreased 7% and, along with the same 3-fold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared to the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.

Aconitine ameliorates cardiomyocyte hypertrophy induced by angiotensin Ⅱ

This paper was aimed to investigate the inhibitory effect of aconitine(AC) on angiotensin Ⅱ(Ang Ⅱ)-induced H9 c2 cell hypertrophy and explore its mechanism of action. The model of hypertrophy was induced by Ang Ⅱ(1×10-6 mol·L-1),and cardiomyocytes were incubated with different concentrations of AC. Western blot was used to quantify the protein expression levels of atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),β-myosin heavy chain(β-MHC),and α-smooth muscle actin(α-SMA). Real-time quantitative PCR(qRT-PCR) was used to quantify the mRNA expression levels of cardiac hypertrophic markers ANP,BNP and β-MHC. In addition,the fluorescence intensity of the F-actin marker,an important component of myofibrils,was detected by using laser confocal microscope. AC could significantly reverse the increase of total protein content in H9 c2 cells induced by Ang Ⅱ; qRT-PCR results showed that AC could significantly inhibit the ANP,BNP and β-MHC mRNA up-regulation induced by AngⅡ. Western blot results showed that AC could significantly inhibit the ANP,BNP and β-MHC protein up-regulation induced by AngⅡ. In addition,F-actin expression induced by Ang Ⅱ could be inhibited by AC,and multiple indicators of cardiomyocyte hypertrophy induced by Ang Ⅱ could be down-regulated,indicating that AC may inhibit cardiac hypertrophy by inhibiting the expression of hypertrophic factors,providing new clues for exploring the cardiovascular protection of AC.

Clinical Implications

Clinical Implications

Effect of chloroquine treatment on cardiac function as well as cardiac atrial natriuretic peptide level in Bcl-2-associated athanogene (BAG) 3 transgenic mice

Effect of chloroquine treatment on cardiac function as well as cardiac atrial natriuretic peptide level in Bcl-2-associated athanogene (BAG) 3 transgenic mice

Aldosterone, Hypertension, and Antihypertensive Therapy: Insights From a General Population

ObjectiveTo investigate the relationships among aldosterone level, use of antihypertensive (anti-HTN) medications, clinical profile, and atrial natriuretic peptide (ANP) level in individuals with HTN. Participants and MethodsIn a community-based cohort, we analyzed aldosterone plasma levels based on the presence (n=477) or absence (n=1073) of HTN. In individuals with HTN, we evaluated circulating aldosterone levels according to the number of anti-HTN drugs used, analyzed the associated clinical characteristics, and determined the relationship to the counterregulatory cardiac hormone ANP. Data were collected from August 25, 1997, through September 5, 2000. ResultsParticipants with HTN had higher serum aldosterone levels than those without HTN (6.4 vs 4.1 ng/dL [to convert to pmol/L, multiply by 27.74]; P<.001). When individuals with HTN were stratified according to the number of anti-HTN medications used, the increase in number of medications (0, 1, 2, and ≥3) was associated with higher aldosterone levels (4.8, 6.4, 7.10, and 7.9 ng/dL, respectively; P=.002), worse metabolic profile, and higher prevalence of cardiovascular, renal, and metabolic disease. In participants with HTN, ANP plasma levels were inversely related to aldosterone levels when the latter was divided into tertiles. ConclusionIn this randomly selected general population cohort, aldosterone levels were higher in individuals with HTN compared with normotensive participants. Aldosterone levels increased with anti-HTN medication use. These findings also suggest a relative ANP deficiency with increasing aldosterone levels and anti-HTN drug use. These studies have pathophysiologic and therapeutic implications for targeting aldosterone in the clinical treatment of HTN.

\u03b2 Cell-specific deletion of guanylyl cyclase A, the receptor for atrial natriuretic peptide, accelerates obesity-induced glucose intolerance in mice

BackgroundThe cardiac hormones atrial (ANP) and B-type natriuretic peptides (BNP) moderate arterial blood pressure and improve energy metabolism as well as insulin sensitivity via their shared cGMP-producing guanylyl cyclase-A (GC-A) receptor. Obesity is associated with impaired NP/GC-A/cGMP signaling, which possibly contributes to the development of type 2 diabetes and its cardiometabolic complications. In vitro, synthetic ANP, via GC-A, stimulates glucose-dependent insulin release from cultured pancreatic islets and β-cell proliferation. However, the relevance for systemic glucose homeostasis in vivo is not known. To dissect whether the endogenous cardiac hormones modulate the secretory function and/or proliferation of β-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in β-cells.MethodsMice with a floxed GC-A gene were bred to Rip-CreTG mice, thereby deleting GC-A selectively in β-cells (β GC-A KO). Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion were monitored in normal diet (ND)- and high-fat diet (HFD)-fed mice. β-cell size and number were measured by immunofluorescence-based islet morphometry.ResultsIn vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from β GC-A KO mice. Concordantly, in vivo, infusion of BNP mildly enhanced baseline plasma insulin levels and glucose-induced insulin secretion in control mice. This effect of exogenous BNP was abolished in β GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in β-cells. Despite this under physiological, ND conditions, fasted and fed insulin levels, glucose-induced insulin secretion, glucose tolerance and β-cell morphology were similar in β GC-A KO mice and control littermates. However, HFD-fed β GC-A KO animals had accelerated glucose intolerance and diminished adaptative β-cell proliferation.ConclusionsOur studies of β GC-A KO mice demonstrate that the cardiac hormones ANP and BNP do not modulate β-cell’s growth and secretory functions under physiological, normal dietary conditions. However, endogenous NP/GC-A signaling improves the initial adaptative response of β-cells to HFD-induced obesity. Impaired β-cell NP/GC-A signaling in obese individuals might contribute to the development of type 2 diabetes.

Bcl-2-associated athanogene 3 (BAG3) is an enhancer of small heat shock protein turnover via activation of autophagy in the heart

Bcl-2-associated athanogene 3 (BAG3) is strongly expressed in both cardiac and skeletal muscle. A recent study showed that BAG3 may play a protective role in muscles. Little is known, however, regarding the detailed role of BAG3 in cardiac muscle. To better understand the functional role of cardiac BAG3 in the heart, we generated transgenic (TG) mice that overexpress BAG3. A decrease in fractional shortening, and the induction of cardiac atrial natriuretic peptide, were observed in BAG3 TG mice. Moreover, a marked reduction in the protein level of small HSPs was detected in BAG3 TG mouse hearts. We analyzed the cardiac small HSP levels when either the ubiquitin-proteasome system (UPS) or the autophagy system (AS) was inhibited in BAG3 TG mice. The protein turnovers of small HSPs by the AS were activated in BAG3 TG mouse hearts. Thus, BAG3 is critical for the protein turnover of small HSPs via activation of autophagy in the heart.

Multiphasic Regulation of Systemic and Peripheral Organ Metabolic Responses to Cardiac Hypertrophy.

Reduced fat oxidation in hypertrophied hearts coincides with a shift of carnitine palmitoyl transferase I from muscle to increased liver isoforms. Acutely increased carnitine palmitoyl transferase I in normal rodent hearts has been shown to recapitulate the reduced fat oxidation and elevated atrial natriuretic peptide message of cardiac hypertrophy. Because of the potential for reduced fat oxidation to affect cardiac atrial natriuretic peptide, and thus, induce adipose lipolysis, we studied peripheral and systemic metabolism in male C57BL/6 mice model of transverse aortic constriction in which left ventricular hypertrophy occurred by 2 weeks without functional decline until 16 weeks (ejection fraction, -45.6%; fractional shortening, -22.6%). We report the first evidence for initially improved glucose tolerance and insulin sensitivity in response to 2 weeks transverse aortic constriction versus sham, linked to enhanced insulin signaling in liver and visceral adipose tissue (epididymal white adipose tissue [WAT]), reduced WAT inflammation, elevated adiponectin, mulitilocular subcutaneous adipose tissue (inguinal WAT) with upregulated oxidative/thermogenic gene expression, and downregulated lipolysis and lipogenesis genes in epididymal WAT. By 6 weeks transverse aortic constriction, the metabolic profile reversed with impaired insulin sensitivity and glucose tolerance, reduced insulin signaling in liver, epididymal WAT and heart, and downregulation of oxidative enzymes in brown adipose tissue and oxidative and lipogenic genes in inguinal WAT. Changes in insulin signaling, circulating natriuretic peptides and adipokines, and varied expression of adipose genes associated with altered insulin response/glucose handling and thermogenesis occurred prior to any functional decline in transverse aortic constriction hearts. The findings demonstrate multiphasic responses in extracardiac metabolism to pathogenic cardiac stress, with early iWAT browning providing potential metabolic benefits.