Brain Natriuretic Peptide Gene Research Articles

Comparison of Protective Effect of Tri-circulator and Coenzyme Q10 on Myocardial Injury and the Mechanism Study by Zebrafish Model.

Tri-Circulator (TC) is a product comprising coenzyme Q10 (CoQ10), Salvia miltiorrhiza, and Panax notoginseng. Individually, each of these constituents has demonstrated protective effects on myocardial injury. The purpose of this study is to evaluate the protective efficacy of TC on heart function and compare the differential effects between CoQ10 and TC. Two myocardial injury models of zebrafish, the hypoxia-reoxygenation model (H/R) and the isoproterenol (ISO, a β-receptor agonist) model, were used in this experiment. The zebrafish subjects were divided into 4 groups: control, H/R, TC, and CoQ10. Heart rate, stroke volume (SV), cardiac output (CO), ejection fraction (EF), fractional area change (FAC), and pericardial height were monitored to assess changes in heart function. The gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was studied as markers of injury/stress. TC significantly suppresses elevated heart rate induced by H/R and prevents the decrease of heart rate induced by ISO. It alleviates the pericardial infusion induced by ISO, whereas CoQ10 does not possess a similar effect. Both TC and CoQ10 significantly inhibit the decline in SV, CO, EF, and FAC induced by H/R and ISO, and suppress the expression of ANP and BNP in cardiomyocytes induced by ISO. It is noteworthy that TC demonstrates a more pronounced effect on EF, FAC, ANP, and BNP gene expression compared to CoQ10. Both TC and CoQ10 have a protective effect on myocardial injury of zebrafish. However, TC exhibits a greater efficacy compared to CoQ10 alone in mitigating myocardial injury.

Chromogranin B in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of the heart failure patients and is associated with high morbidity and mortality. More fundamental knowledge about this heterogeneous disease and the underlying pathomechanisms is needed in order to find effective therapeutic targets, as they are still lacking. Previously, we found that Chromogranin B is expressed in ventricular cardiomyocytes and shapes cytosolic calcium transients via the inositol 1,4,5-trisphophate receptor (IP3R) with impact on brain natriuretic peptide (BNP) gene transcription.

NRSF/REST-Mediated Epigenomic Regulation in the Heart: Transcriptional Control of Natriuretic Peptides and Beyond.

Simple SummaryReactivation of the fetal cardiac gene program, such as those encoding atrial and brain natriuretic peptides (ANP and BNP, respectively), is a characteristic feature of failing hearts. We previously revealed that a transcriptional repressor, neuron-restrictive silencer factor (NRSF), also called repressor element-1-silencing transcription factor (REST), plays a crucial role in the transcriptional control of ANP, BNP and other fetal cardiac genes through collaboration with various other transcription factors to maintain physiological cardiac function and electrical stability. Increased production of ANP and BNP prevents the progression of heart failure, but reactivation of Gαo and fetal-type cardiac ion channels (T-type Ca2+ and HCN channels) leads to deteriorated cardiac function and lethal arrhythmias observed in mice with disturbed NRSF function. Epigenetic regulators with which NRSF forms a complex modify histone acetylation and methylation, thereby participating in NRSF-mediated transcriptional regulation. Further comprehensive studies will lead to clarification of the molecular mechanisms underlying the development of cardiac dysfunction and heart failure.Reactivation of fetal cardiac genes, including those encoding atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), is a key feature of pathological cardiac remodeling and heart failure. Intensive studies on the regulation of ANP and BNP have revealed the involvement of numerous transcriptional factors in the regulation of the fetal cardiac gene program. Among these, we identified that a transcriptional repressor, neuron-restrictive silencer factor (NRSF), also named repressor element-1-silencing transcription factor (REST), which was initially detected as a transcriptional repressor of neuron-specific genes in non-neuronal cells, plays a pivotal role in the transcriptional regulation of ANP, BNP and other fetal cardiac genes. Here we review the transcriptional regulation of ANP and BNP gene expression and the role of the NRSF repressor complex in the regulation of cardiac gene expression and the maintenance of cardiac homeostasis.

Diabetic cardiomyopathy was attenuated by cinnamon treatment through the inhibition of fibro-inflammatory response and ventricular hypertrophy in diabetic rats.

Diabetic cardiomyopathy (DCM) is a chronic complication of diabetes that emphasizes the urgency of developing new drug therapies. With an illustrious history in traditional medicine to improve diabetes, cinnamon has been shown to possess blood lipids lowering effects and antioxidative and anti-inflammatory properties. However, the extent to which it protects the diabetic heart has yet to be determined. Forty-eight rats were administered in the study and grouped as: control; diabetic; diabetic rats given 100, 200, or 400 mg/kg cinnamon extract, metformin (300 mg/kg), valsartan (30 mg/kg), or met/val (combination of both drugs), via gavage for six weeks. Fasting blood sugar (FBS) and markers of cardiac injury including creatine kinase-muscle/brain (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were evaluated in blood samples. Malondialdehyde (MDA) levels, the total contents of thiol, superoxide dismutase (SOD), and catalase (CAT) activities were measured. Histopathology study and gene expression measurement of angiotensin II type 1 receptor (AT1), atrial natriuretic peptide (ANP), beta-myosin heavy chain (β-MHC), and brain natriuretic peptide (BNP) were done on cardiac tissue. FBS and cardiac enzyme indicators were reduced in all treated groups. A reduction in MDA level and enhancement in thiol content alongside with increase of SOD and CAT activities were observed in extract groups. The decrease of inflammation and fibrosis was obvious in treated groups, notably in the high-dose extract group. Furthermore, all treated diabetic groups showed a lowering trend in AT1, ANP, β-MHC, and BNP gene expression. Cinnamon extract, in addition to its hypoglycemic and antioxidant properties, can prevent diabetic heart damage by alleviating cardiac inflammation and fibrosis. PRACTICAL APPLICATIONS: This study found that cinnamon extract might protect diabetic heart damage by reducing inflammation and fibrosis in cardiac tissue, in addition to lowering blood glucose levels and increasing antioxidant activity. Our data imply that including cinnamon in diabetic participants' diets may help to reduce risk factors of cardiovascular diseases.

Relationship Between Circulating MicroRNAs and Left Ventricular Hypertrophy in Hypertensive Patients.

ObjectiveLeft ventricular hypertrophy (LVH) is a common complication of hypertension and microRNAs (miRNAs) are considered to play an important role in cardiac hypertrophy development. This study evaluated the relationship between circulating miRNAs and LVH in hypertensive patients.MethodsTwo cohorts [exploratory (n = 42) and validation (n = 297)] of hypertensive patients were evaluated by clinical, laboratory and echocardiography analysis. The serum expression of 754 miRNAs in the exploratory cohort and 6 miRNAs in the validation cohort was evaluated by the TaqMan OpenArray® system and quantitative polymerase chain reaction, respectively.ResultsAmong the 754 analyzed miRNAs, ten miRNAs (miR-30a-5p, miR-let7c, miR-92a, miR-451, miR-145-5p, miR-185, miR-338, miR-296, miR-375, and miR-10) had differential expression between individuals with and without LVH in the exploratory cohort. Results of multivariable regression analysis adjusted for confounding variables showed that three miRNAs (miR-145-5p, miR-451, and miR-let7c) were independently associated with LVH and left ventricular mass index in the validation cohort. Functional enrichment analysis demonstrated that these three miRNAs can regulate various genes and pathways related to cardiac remodeling. Furthermore, in vitro experiments using cardiac myocytes demonstrated that miR-145-5p mimic transfection up-regulated the expression of brain and atrial natriuretic peptide genes, which are markers of cardiac hypertrophy, while anti-miR-145-5p transfection abrogated the expression of these genes in response to norepinephrine stimulus.ConclusionsOur data demonstrated that circulating levels of several miRNAs, in particular miR-145-5p, miR-451, and let7c, were associated with LVH in hypertensive patients, indicating that these miRNAS may be potential circulating biomarkers or involved in hypertension-induced LV remodeling.

Research on the Correlation between Plasma BNP and the Condition and Prognosis of Chronic Heart Failure

This study aimed to analyze the correlation between the level of brain natriuretic peptide (BNP) and the condition and prognosis of chronic heart failure (CHF). For this purpose, between January 2017 and July 2020, we recruited a total of 120 CHF patients who were treated in Cangzhou Central Hospital into this study, consisting of 40 patients in NYHA II, 40 in NYHA III and 40 in NYHA IV, and simultaneously, 40 subjects with normal heart function were enrolled into the control group. General data were collected from the patients and subjects, and laboratory tests regarding the BNP level, LVEDD and LVEF were carried out. Correlation between plasma level of BNP and the evaluation of condition and prognosis of CHF was also analyzed. For further evaluation, the expression of BNP gene expression was considered in the femoral blood of participants by the Real-time PCR technique. The results showed that comparison over the clinical data of subjects among these groups showed no significant difference (P > 0.05). In the research group, the averages of LVEDD and BNP in plasma were (58.53±3.75) mm and (5089.86±22.39) pg/mL, significantly higher than those in the control group, while the LVEF was (45.66±3.42) %, which was lower than that in the control group (all P < 0.05). For the subgroup comparison, as the NYHA class augmented, patients also had a significant increase in the mortality rate and the difference among subgroups had statistical significance (P < 0.05). Furthermore, with 442 pg/mL as a critical point for BNP, patients in the research group were further divided into the BNP>442 pg/mL group and BNP ≤442pg/mL group, and the statistical analysis revealed that in the BNP>442 pg/mL group, the incidence rate of cardiovascular events, re-hospitalization rate and mortality rate were 53.53%, 14.14% and 7.07%, which were all significantly higher than those in the BNP ≤ 442 pg/mL group (all P < 0.05). Also, BMP gene expression was increased in NYHA II, NYHA III, and NYHA IV groups compared to the control group. However, this increase was statistically significant in the NYHA III group (P <0.05) and in the NYHA IV group (P <0.01) compared to the control group. In conclusion, the level of BNP in plasma can reflect the condition of CHF and is critical to the clinical diagnosis, treatment and prognosis evaluation and evaluation of the BNP gene confirmed the result. Thus, it is worth being promoted in clinical practice.

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.

The regulation of BNP transcription and DNA methylation modification in anticancer drug-induced cardiomyocyte toxicity.

Background) Genomic DNA, which contains all of the genetic information, is damaged by a variety of endogenous and environmental factors such as genotoxic chemicals, ionizing radiation and UV light. Consequently, the DNA repair process is constantly active as it responds to damage in the DNA structure. Not only cardiotoxicity of anticancer drug treatment but also ischemic heart disease and heart failure associated with overloaded pressure interfere with DNA damage response and DNA repair regulation in cardiomyocytes. We have reported that anticancer drug treatment causes a transient decrease in plasma brain natriuretic peptide (BNP) levels, but the mechanism of this decrease is unknown. In the present study, to clarify this molecular mechanism, we analyzed mouse hearts treated with anticancer drugs. Methods) C57BL/6 mice were treated with cisplatin (16 mg/kg, ip), and then BNP gene expression and DNA methylation in the heart were examined. Results) In cisplatin-treated mice, there was a transient decrease in BNP gene expression and an increase in DNA methylation of the BNP promoter region. Furthermore, DNA methyltransferase type 1 (DNMT1) was found to affect this DNA methylation. Conclusions) In cisplatin-treated mice, cardiac BNP transcription was repressed by DNA methylation. DNMT1 was suggested to be involved in this DNA methylation modification.

Metformin suppresses phenylephrine-induced hypertrophic responses by inhibiting p300-HAT activity in cardiomyocytes

IntroductionHeart failure is the final pathway for a wide spectrum of myocardial stress, including hypertension and myocardial infarction. However, the potential effects of metformin on cardiac hypertrophy are still unclear. PurposeThe purpose of this study was to investigate whether metformin leads to suppression of hypertrophic responses in cardiomyocytes. Methods and resultsTo investigate whether metformin inhibited p300-histone acetyltransferase (HAT), we performed an in vitro HAT assay. Metformin directly inhibited p300-mediated acetylation of histone-H3K9. To examine the effects of metformin on hypertrophic responses, cardiomyocytes prepared from neonatal rats were treated with metformin and stimulated with saline or phenylephrine (PE), a α1-adrenergic agonist for 48 h. PE stimulus showed an increase in cell size, myofibrillar organization, expression of the endogenous atrial natriuretic factor and brain natriuretic peptide genes, and acetylation of histone-H3K9 compared with saline-treated cells. These PE-induced changes were inhibited by metformin. Next, to examine the effect of metformin on p300-mediated hypertrophy, cardiomyocytes were transfected with expression vector of p300. Metformin significantly suppressed p300-induced hypertrophic responses and acetylation of histone-H3K9. ConclusionsThe study demonstrates that metformin can suppress PE-induced and p300-mediated hypertrophic responses. Metformin may be useful for the treatment of patients with diabetes and heart failure.

Sex-dependent right ventricular hypertrophic gene changes after methamphetamine treatment in mice

Methamphetamine (MA) abuse is associated with the development of pulmonary arterial hypertension (PAH) and subsequent right ventricular failure. A recent clinical study demonstrated that female sex is a major risk factor for MA-induced PAH. The mechanisms associated with increased prevalence and severity of MA-induced PAH in females are still unclear. We hypothesized that MA may promote changes in gene expression in the right ventricle contributing to the development and/or worsening of PAH in females. Male and female C57BL/6 mice were treated with either MA or vehicle. Right and left ventricular systolic pressures (RVSP and LVSP, respectively) were assessed and tissue samples were collected for gene expression and histology. LVSP and RVSP were not affected by MA in either males or females. Right ventricular hypertrophy was significantly increased by MA in females but it was not affected by MA in males. In the female mice, MA-induced right ventricular hypertrophy was associated with increased expression of brain natriuretic peptide gene and members of the TGF-β receptor signaling pathway such as TGF-β receptor-1, smad3 and smad7. In male mice, there were no changes in right ventricular gene expression. Our results suggest that MA caused right ventricular hypertrophy in female mice, but not in males and that this was associated with an increase in hypertrophic genes. The right ventricular hypertrophy was not dependent on increased RVSP suggesting a direct effect of MA on the right ventricle. If this translates to PAH patients, it might explain the poor outcome observed in MA-associated female PAH patients.

Functional analysis of the brain natriuretic peptide gene for high-altitude adaptation in Tibetan pigs.

High-altitude adaptation in Tibetan pigs (TP) is associated with positively-selected genes. The brain natriuretic peptide (BNP) gene is critical in the regulation of cardiovascular homeostasis and energy metabolism. The present study was conducted to identify the function of BNP for high-altitude adaptations in TP. RT-qPCR and western blotting results indicated that BNP expression could be upregulated when the pigs (especially for the Tibetan pigs) were raised to high altitude. In the 5' flanking region, three polymorphic sites, A-1964G, C-1780G, and T-940C were detected, and the genotype distribution of C-1780G was significantly different between the highland (TP) and lowland (Diannan small-eared pig; Yorkshire pig) breeds. The site of C-1780G was in active promoter regions identified using the luciferase reporter gene system, and the fragment with allele G had higher transcriptional activity than that with allele C. The TP population had a higher frequency of allele G than the two lowland breeds. Our results collectively demonstrated that the G allele of C-1780G in the BNP gene may be advantageous for high-altitude adaptation in pigs through upregulating BNP expression. Our findings provide information that helps toward a comprehensive understanding of the mechanism underlying the involvement of the BNP gene in high-altitude adaptation.

Features of hemodynamics in the comorbid course of essential hypertension and type 2 diabetes in men, residents of Podillia, carriers of polymorphic variants of the brain natriuretic peptide gene

Essential hypertension (EH) and type 2 diabetes (T2D) are important risk factors for the development of chronic heart failure (CHF). The early detection of CHF, especially under comorbidity, remains a challenge. To solve it in today’s conditions are used not only instrumental diagnostic methods (Echo-CG), but also the assessment of plasma levels of biomarker – brain natriuretic peptide (BNP), the expression of which is determined by the corresponding gene (locus T-381C) and may depend on its structural organization. It is proved that deregulation of the natriuretic peptide system (NP) is an important factor in the initiation and progression of myocardial dysfunction and energy imbalance, but the role of genetic preconditions for these disorders, including the peculiarities of polymorphic variants of the most physiologically significant gene is still not enough clear. The aim of the work was to investigate the presence of associations between indicators of systemic and intracardiac hemodynamic and the carrier of polymorphic variants of the BNP gene (T-381C) in men, residents of Podillia with the comorbid course of EH 2 and type 2 diabetes mellitus. We examined 132 middle-age men: 62 patients with EH 2 and chronic heart failure (CHF) 0-I functional classes (FC) according to NYHA Classification and 70 - with EH 2 combined with T2D and CHF FC I-II. Patients with EH 2 included in the first group and patients with EH 2 and T2D included in the second group of comparison. Parameters of intracardiac hemodynamics were determined on the basis of pulsed Doppler echocardiography. The genomic DNA of the BNP gene (T-381C) for the determination of its alleles was isolated by PCR. The mathematical processing was performed using the standard statistical package Statistica 10. We calculated the primary statistical indicators, identified differences between groups on statistical signs, performed correlation and discriminant analysis. The calculation of the relative risk with a 95% confidence interval was performed using an online calculator (https://medstatistic.ru/calculators/calcrisk.html). Among men living in Podillya with EH, both in the presence and absence of diabetes mellitus 2, the T381C genotype of the BNP gene (p>0.05) dominates. In the group of comorbid patients diastolic dysfunction of the left ventricle (DD LV) was diagnosed in 90% of people (n=63), while in the isolated course of EH it was found only in 43.55% (n=28). Although among homozygotes T381T BNP gene its symptoms were 100% (n=24), and among carriers of the C allele – in 84.78% (n=39) of patients. Carriers of the T381T genotype of the BNP gene dominated among persons with DD grade II: 41.66% against 10.87% of carriers of the C allele (p<0.05), while among persons with DD LV grade I there were more carriers of the C allele. Homozygous T381T genotype with EH 2 and T2D had a higher level of pulse blood pressure (p<0,01), a higher probability of developing eccentric left ventricular hypertrophy (p≤0.05) and more pronounced diastolic changes in the myocardium, as compared with carriers of the C allele and can be allocated to the priority group of observation for the organization of targeted measures aimed at preventing the development and progression of CHF.

The role of the brain natriuretic peptide gene polymorphism in the diagnostic use of the biomarker in myocardial dysfunction in men, residents of Podillya with comorbid essential hypertension and type 2 diabetes mellitus

There is a growing interest in the early detection of signs of myocardial dysfunction, especially in comorbid patients for timely prevention of progression of disease, reducing the risk of complications, improving their quality of life. The aim of the work was to optimize the diagnosis of myocardial dysfunction in men, residents of Podillya, taking into account the plasma concentration of brain natriuretic peptide (BNP) and polymorphism of the corresponding gene under conditions of comorbidity of essential hypertension (EH) with left ventricular hypertrophy (LVH) and type 2 diabetes mellitus (T2D). We examined 211 men: 79 persons without the signs of cardiovascular diseases, 62 patients with EH 2 and chronic heart failure (CHF) 0-I functional classes (FC) according to NYHA Classification and 70 – with EH 2 combined with T2D and CHF FC I-II. The examination included the determination of plasma concentration of BNP, the brain natriuretic peptide gene polymorphism (polymorphic locus T-381C), indices of doppler-echocardiography. The mathematical processing was performed using the standard statistical package Statistica 10. During the study, we calculated the primary statistical indicators, identified differences between groups on statistical grounds, made correlation and discriminant analysis. Diastolic dysfunction (DD) of the left ventricle (LV) was diagnosed in 45.16% of patients in the group with EH 2, and 90% in the group of comorbid patients. It was determined that men, residents of Podillya, with presence and absence of T2D, have dominating T381C genotype of the BNP gene (p>0.05). Lower plasma concentration of BNP that is peculiar for homozygous T381T genotype, in comparison with carriers of allele C of BNP gene and the average values of this biomarker in patients with DD may affect its informativeness in the diagnosis of myocardial dysfunction and requires a lower level of diagnosis. Appropriate borderline levels of BNP were determined for early diagnosis of DD in carriers of polymorphic variants of the BNP gene in men, residents of Podillya, with comorbid course of EH 2 and T2D. It is recommended to determine the genotype of the corresponding gene (polymorphic locus T-381C) and plasma level of BNP and focus on the calculated borderline levels of BNP to optimize the diagnosis of myocardial dysfunction in comorbid patients with EH 2 and T2D. For carriers of the T381T genotype it is ≥55.57 pg/ml, for carriers of the C allele (heterozygous T381C and homozygous C381C) of the BNP gene it is ≥69.13 pg/ml.

Crosstalk between cardiomyocytes and noncardiomyocytes is essential to prevent cardiomyocyte apoptosis induced by proteasome inhibition

Heart is a multi-cellular organ made up of various cell types interacting with each other. Cardiomyocytes may benefit or suffer from crosstalk with noncardiomyocytes in response to diverse kinds of cardiac stresses. Proteasome dysfunction is a common cardiac stress which causes cardiac proteotoxicity and contributes to cardiac diseases such as heart failure and myocardial infarction. The role of crosstalk between cardiomyocytes and noncardiomyocytes in defense of cardiac proteotoxicity remains unknown. Here, we report a cardiomyocyte-specific survival upon proteasome inhibition in a heterogeneous culture consisting of cardiomyocytes and other three major cardiac cell types. Conversely, cardiomyocyte apoptosis is remarkably induced by proteasome inhibition in a homogeneous culture consisting of a majority of cardiomyocytes, demonstrating an indispensable role of noncardiomyocytes in the prevention of cardiomyocyte apoptosis resulting from proteasome inhibition. We further show that cardiomyocytes express brain natriuretic peptide (BNP) as an extracellular molecule in response to proteasome inhibition. Blockade of BNP receptor on noncardiomyocytes significantly exacerbated the cardiomyocyte apoptosis, indicating a paracrine function of cardiomyocyte-released extracellular BNP in activation of a protective feedback from noncardiomyocytes. Finally, we demonstrate that proteasome inhibition-activated transcriptional up-regulation of BNP in cardiomyocytes was associated with the dissociation of repressor element 1 silencing transcription factor (REST)/ histone deacetylase 1 (HDAC1) repressor complex from BNP gene promoter. Consistently, the induction of BNP could be further augmented by the treatment of HDAC inhibitors. We conclude that the crosstalk between cardiomyocytes and noncardiomyocytes plays a crucial role in the protection of cardiomyocytes from proteotoxicity stress, and identify cardiomyocyte-released BNP as a novel paracrine signaling molecule mediating this crosstalk. These findings provide new insights into the key regulators and cardioprotective mechanism in proteasome dysfunction-related cardiac diseases.

Cardiac hypertrophy or failure? - A systematic evaluation of the transverse aortic constriction model in C57BL/6NTac and C57BL/6J substrains.

BackgroundThe mouse model of transverse aortic constriction (TAC) has been widely used as a cardiac stress in the investigation of the molecular mechanisms of cardiac hypertrophy. Recently, the International Knockout Mouse Consortium has selected the C57BL/6NTac (BL/6N) mouse strain to generate null alleles for all mouse genes; however, a range of genetic and cardiac phenotypic differences have been reported between this substrain and the commonly used C57BL/6J (BL/6J) substrain. It has been reported by Garcia-Menendez and colleagues that 12-week C57BL/6NTac mice are susceptible to heart failure but little is known about the cardiac remodeling in this substrain as cardiac function progresses from compensation to decompensation.MethodsBL/6J and BL/6N mice were subjected to pressure overload via TAC. The impact of both age and duration of cardiac pressure overload induced by TAC on cardiac remodelling were systematically assessed.ResultsOur data showed that BL/6N mice developed eccentric hypertrophy with age- and time-dependent deterioration in cardiac function, accompanied by considerable interstitial fibrosis. In contrast, BL/6J mice were more resilient to TAC-induced cardiac stress and developed variable cardiac phenotypes independent of age and the duration of pressure overload. This was likely due to the greater variability in pre-TAC aortic arch dimension as measured by echocardiography. In addition to increased expression of brain natriuretic peptide and collagen gene type 1 and 3, BL/6N mice also had greater angiotensin II type 2 receptor (AT2R) gene expression than BL/6J counterparts at baseline and after 2-weeks TAC, which may contribute to the exacerbated interstitial fibrosis.ConclusionsBL/6N and BL/6J mice have very different responses to TAC stimulation and these differences should be taken into consideration when using the substrains to investigate the mechanisms of hypertrophy and heart failure.

Association of brain natriuretic peptide gene polymorphisms with chronic obstructive pulmonary disease complicated with pulmonary hypertension and its mechanism.

Objective: To examine the association between brain natriuretic peptide (BNP) gene single nucleotide polymorphisms (SNPs) and chronic obstructive pulmonary disease (COPD) and COPD with pulmonary hypertension (PH) and to analyze its mechanism. Methods: The genotypes of BNP at the rs198389, rs6668352, and rs198388 loci in 339 patients with COPD (205 in the COPD/PH− group and 134 in the COPD/PH+ group) and 125 healthy subjects were detected by PCR/Sanger sequencing. The serum levels of BNP, fibrinogen (Fbg), and Apelin were measured in all subjects by ELISA. Results: The BNP rs198389 locus G allele, rs6668352 locus A allele, and 198388 locus T allele were high risk factors for COPD (P<0.001). Logistics regression analysis showed that BNP rs198389 locus G allele, rs6668352 locus A allele, and rs198388 locus T allele were high risk factors for PH in COPD patients (all P<0.001). The levels of the serum BNP and Fbg protein in the control group, COPD/PH− group, and COPD/PH+ group increased successively, and the expression levels of Apelin protein decreased successively (all P<0.001). The BNP and Fbg protein levels in the wild-type, heterozygote, and mutant homozygote in BNP rs198389, rs6668352, and rs198388 loci increased successively, and the serum Apelin protein levels decreased successively (all P<0.001). Conclusion: The polymorphisms of BNP at the rs198389, rs6668352, and rs198388 loci are associated with the occurrence of COPD and COPD with PH, and the occurrence may be related to the abnormal expression level of BNP, Fbg, and Apelin protein in the serum.

Anti-fibrotic Actions of Roselle Extract in Rat Model of Myocardial Infarction.

Heart failure-associated morbidity and mortality is largely attributable to extensive and unregulated cardiac remodelling. Roselle (Hibiscus sabdariffa) calyces are enriched with natural polyphenols known for antioxidant and anti-hypertensive effects, yet its effects on early cardiac remodelling in post myocardial infarction (MI) setting are still unclear. Thus, the aim of this study was to investigate the actions of roselle extract on cardiac remodelling in rat model of MI. Male Wistar rats (200-300g) were randomly allotted into three groups: Control, MI, and MI + Roselle. MI was induced with isoprenaline (ISO) (85mg/kg, s.c) for two consecutive days followed by roselle treatment (100mg/kg, orally) for 7days. Isoprenaline administration showed changes in heart weight to body weight (HW/BW) ratio. MI was especially evident by the elevated cardiac injury marker, troponin-T, and histological observation. Upregulation of plasma levels and cardiac gene expression levels of inflammatory cytokines such as interleukin (IL)-6 and IL-10 was seen in MI rats. A relatively high percentage of fibrosis was observed in rat heart tissues with over-expression of collagen (Col)-1 and Col-3 genes following isoprenaline-induced MI. On top of that, cardiomyocyte areas were larger in heart tissues of MI rats with upregulation of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression, indicating cardiac hypertrophy. Interestingly, roselle supplementation attenuated elevation of plasma troponin-T, IL-6, IL10, and gene expression level of IL-10. Furthermore, reduction of cardiac fibrosis and hypertrophy were observed. In conclusion, roselle treatment was able to limit early cardiac remodelling in MI rat model by alleviating inflammation, fibrosis, and hypertrophy; hence, the potential application of roselle in early adjunctive treatment to prevent heart failure.

Type 1 diabetes mellitus induces structural changes and molecular remodelling in the rat kidney.

There is much evidence that diabetes mellitus (DM)-induced hyperglycemia (HG) is responsible for kidney failure or nephropathy leading to cardiovascular complications. Cellular and molecular mechanism(s) whereby DM can damage the kidney is still not fully understood. This study investigated the effect of streptozotocin (STZ)-induced diabetes (T1DM) on the structure and associated molecular alterations of the isolated rat left kidney following 2 and 4months of the disorder compared to the respective age-matched controls. The results revealed hypertrophy and general disorganized architecture of the kidney characterized by expansion in glomerular borders, tubular atrophy and increased vacuolization of renal tubular epithelial cells in the diabetic groups compared to controls. Electron microscopic analysis revealed ultrastructural alterations in the left kidney highlighted by an increase in glomerular basement membrane width. In addition, increased caspase-3 immunoreactivity was observed in the kidney of T1DM animals compared to age-matched controls. These structural changes were associated with elevated extracellular matrix (ECM) deposition and consequently, altered gene expression profile of ECM key components, together with elevated levels of key mediators (MMP9, integrin 5α, TIMP4, CTGF, vimentin) and reduced expressions of Cx43 and MMP2 of the ECM. Marked hypertrophy of the kidney was highlighted by increased atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression. These changes also correlated with increased TGFβ1 activity, gene expression in the left kidney and elevated active TGFβ1 in the plasma of T1DM rats compared to control. The results clearly demonstrated that TIDM could elicit severe structural changes and alteration in biochemical markers (remodelling) in the kidney leading to diabetic nephropathy (DN).

Thioredoxin 2 Offers Protection against Mitochondrial Oxidative Stress in H9c2 Cells and against Myocardial Hypertrophy Induced by Hyperglycemia

Mitochondrial oxidative stress is thought to be a key contributor towards the development of diabetic cardiomyopathy. Thioredoxin 2 (Trx2) is a mitochondrial antioxidant that, along with Trx reductase 2 (TrxR2) and peroxiredoxin 3 (Prx3), scavenges H2O2 and offers protection against oxidative stress. Our previous study showed that TrxR inhibitors resulted in Trx2 oxidation and increased ROS emission from mitochondria. In the present study, we observed that TrxR inhibition also impaired the contractile function of isolated heart. Our studies showed a decrease in the expression of Trx2 in the high glucose-treated H9c2 cardiac cells and myocardium of streptozotocin (STZ)-induced diabetic rats. Overexpression of Trx2 could significantly diminish high glucose-induced mitochondrial oxidative damage and improved ATP production in cultured H9c2 cells. Notably, Trx2 overexpression could suppress high glucose-induced atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression. Our studies suggest that high glucose-induced mitochondrial oxidative damage can be prevented by elevating Trx2 levels, thereby providing extensive protection to the diabetic heart.

Comparison between Brain Natriuretic Peptide and Calcitonin Gene Related Peptide in Children with Dilated Cardiomyopathy

Background: Dilated cardiomyopathy (DCM) is revealed with the left ventricular dilatation and systolic dysfunction. This study was performed to determine the level of Calcitonin Gene Related Peptide (CGRP) and Brain Natriuretic Peptide (BNP) in children with dilated cardiomyopathy and controls and comparison of these two biomarkers in patients. Materials and Methods: This case-control study was performed from April 2014 to March 2015 on patients with DCM. The levels of BNP and CGRP were measured by ELISA and final amounts of biomarkers were compared with echocardiographic finding.37 DCM patients compared with 30 healthy children selected randomly from those who referred to the hospital for routine checkup. Results: In this study the mean age was 10.567± 5.50 and 12.135 ± 4.626 years for controls and cases, respectively (P=0.321). The majority of echocardiography indices in the left and right heart had different means in case and controls (P<0.05). Means of BNP were 213.814 ± 309.601 and 2.76± 1.013 for case and control groups, respectively (P< 0.001). Means of CGRP were 2.278±1.586 and 1.488±0.501 for case and control groups, respectively (P = 0.001). In the dilated cardiomyopathy children however, no significant relationship was observed between CGRP level and Ross classification, but observed a significant association between Ross classification and BNP (Chi square = 15.85 and P=0.001). Conclusion:The present research was performed on DCM patients and showed that most echocardiographic parameters, mean of CGRP and mean of BNP increased in patients compared to healthy children. The severity of illness based on the Ross classification showed significant and positive correlation with BNP level but not with CGRP. Probably could be concluded that, BNP would be a better biomarker in DCM patients.