Atrial Natriuretic Peptide Research Articles

Artemisinin Attenuates Isoproterenol-induced Cardiac Hypertrophy via the ERK1/2 and p38 MAPK Signaling Pathways.

Artemisinin (ART) is mainly derived from Artemisia annua, a traditional Chinese medicinal plant, and has been found to affect cellular biochemical processes, such as proliferation, angiogenesis, and apoptosis, in addition to its antimalarial properties. However, its effect on cardiac hypertrophy and the underlying mechanisms remain unclear. This study aimed to investigate the effect of ART on cardiac hypertrophy and explore its possible mechanisms. A rat model was established by intraperitoneal injection of isoproterenol (ISO) for 3 days, and the degree of myocardial hypertrophy was compared among 5 groups: a control (CON) group, an ISO group, and groups treated with different doses of ART (7 mg/kg/d, 35 mg/kg/d, and 75 mg/kg/d). Echocardiography was used to evaluate cardiac function and structure. The cross-sectional area of cardiomyocytes was measured by hematoxylin and eosin (H&E) staining. The heart weight (HW), body weight (BW), and tail length were measured, and the HW/tail length ratio and the HW/BW ratio were calculated. H9c2 rat cardiomyocytes were cultured, and different amounts of ART were added 2 hours before ISO stimulation. Phalloidin staining was used to evaluate the degree of cell hypertrophy. The levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were quantified in rat plasma and cell supernatant using enzyme-linked immunosorbent assay (ELISA), while the expression levels of p- ERK1/2, p-JNK, and p-p38 MAPK were assessed in the myocardium and H9c2 cells via western blot analysis. Intragastric administration of ART at a dosage of 35 mg/kg/d or over mitigated the early-stage cardiac hypertrophy induced by ISO in rats led to a reduction in left ventricular posterior wall diastolic thickness, interventricular septal thickness at diastole, lowered ANP and BNP levels, as well as a decrease in HW/tail length and HW/BW ratio. In vitro studies demonstrated that ART at a concentration of 100 μM inhibited ISO-mediated hypertrophy of H9c2 cells. The ISO group showed a higher p-ERK/GAPDH ratio and p-p38 MAPK/GAPDH ratio than the control group both in vivo and in vitro. Although the p-JNK/GAPDH ratio was increased in the ISO group, there was no statistical difference. The p-ERK/GAPDH and p-p38/GAPDH ratios were significantly lower in the ART group than in the ISO group. The mechanism of ART against cardiac hypertrophy was related to inhibition of the ERK1/2 and p38 MAPK signaling pathways.

Studying the possibilities of pharmacological correction of hypoxia-induced pulmonary hypertension using a phenolic compound with a laboratory cypher KUD975

The aim of our work was to study a pharmacological activity of a selective arginase-2 and thrombin inhibitor from a phenolic compounds group with a laboratory cypher KUD975 on a model of arterial pulmonary hypertension induced by hypoxia.Materials and methods. To simulate pulmonary hypertension (РН), animals were placed in a normobaric hypoxic chamber and subjected to 5 weeks of hypoxia with an oxygen content of 10% in the air. After 3 weeks of hypoxia, the animals were administered with the test compound KUD975 (intragastrically, at a dose of 2 mg/kg once a day for 2 weeks). L-norvaline (intragastrically, 20 mg/kg) was used as a reference drug. To assess the development and correction of РН, measurements of cardiohemodynamics, analysis of blood gas composition, study of the number of circulating endothelial precursor cells (EPCs), quantitative PCR assessing the expression of mRNA VEGF-R2, SGF-1 (stromal growth factor-1) and MCP-1 (monocyte chemoattractant protein-1). Next, a histological examination of the lungs and heart was performed, the degree of pulmonary edema and the concentration of cardiotrophin-1 and atrial natriuretic peptide were assessed.Results. The administration of the studied phenolic compound with laboratory cypher KUD975, as well as the reference drug L-norvaline, led to a decrease in the right ventricular systolic pressure against the background of modeling РН. The present study shows a more than twice-fold decrease in the number of circulating (EPCs) in the animals group with modeling a hypoxia-induced circulatory РН (171.3±12.1) in comparison with the group of intact animals (296.1±31.7; p=0.0018). The recovery of EPCs was noted in the animals group administered with KUD-975 and L-norvaline, up to 247.5±34.2 (p=0.0009 compared with a pulmonary arterial hypertension (PAH) and 235.6±36.4 (p=0.008 compared to PAH), respectively. The studied compounds had a protective effect by statistically significantly increasing the expression of VEGF-R2 mRNA and decreasing the expression of SGF-1 mRNA, reducing the lung moisture coefficient and the concentrations of cardiotrophin-1 and atrial natriuretic peptide and preventing vascular remodeling caused by hypoxia.Conclusion. When studying the pharmacological activity, it was shown that the phenolic compound with the laboratory cypher KUD975 normalizes hemodynamic parameters, reduces the signs of remodeling of the heart and pulmonary vessels and has a pronounced endothelial protective effect on the model of hypoxia-induced РН, and is superior to the activity of the reference drug L-norvaline.

Evaluation of Tyrosine Kinase Inhibitors Loaded Injectable Hydrogels for Improving Connexin43 Gap Junction Intercellular Communication.

Myocardial infarction (MI) is one of the leading causes of death in the developed world, and the loss of cardiomyocytes plays a critical role in the pathogenesis of heart failure. Implicated in this process is a decrease in gap junction intercellular communication due to remodeling of Connexin43 (Cx43). We previously identified that intraperitoneal injection of the Pyk2 inhibitor PF4618433 reduced infarct size, maintained Cx43 at the intercalated disc in left ventricle hypertrophic myocytes, and improved cardiac function in an MI animal model of heart failure. With the emergence of injectable hydrogels as a therapeutic toward the regeneration of cardiac tissue after MI, here, we provide proof of concept that the release of tyrosine kinase inhibitors from hydrogels could have beneficial effects on cardiomyocytes. We developed an injectable hydrogel consisting of thiolated hyaluronic acid and P123-maleimide micelles that can incorporate PF4618433 as well as the Src inhibitor Saracatinib and achieved sustained release (of note, Src activates Pyk2). Using neonatal rat ventricular myocytes in the presence of a phorbol ester, endothelin-1, or phenylephrine to stimulate cardiac hypertrophy, the release of PF4618433 from the hydrogel had the same ability to decrease Cx43 tyrosine phosphorylation and maintain Cx43 localization at the plasma membrane as when directly added to the growth media. Additional beneficial effects included decreases in apoptosis, the hypertrophic marker atrial natriuretic peptide (ANP), and serine kinases upregulated in hypertrophy. Finally, the presence of both PF4618433 and Saracatinib further decreased the level of ANP and apoptosis than each inhibitor alone, suggesting that a combinatorial approach may be most beneficial. These findings provide the groundwork to test if tyrosine kinase inhibitor release from hydrogels will have a beneficial effect in an animal model of MI-induced heart failure.

Atrial natriuretic peptide protects against gut barrier injury through PLC-γ1/ROS feedback loop in rats following traumatic hemorrhagic shock

Introduction The mechanisms underlying the protective effects of atrial natriuretic peptide (ANP) on the gut barrier during traumatic hemorrhagic shock (THS) remain elusive. This study aimed to explore the potential role of ANP in safeguarding against gut barrier dysfunction after THS, focusing on the PLC-γ1/ROS feedback loop. Methods In our THS rat model, we randomly allocated male Sprague-Dawley rats to receive intravenous ANP with or without a concurrent NADPH oxidase/p38 MAPK inhibitor during the shock phase. After 24 h, we assessed circulatory and jejunal ANP, ROS, intestinal tight junction proteins, and apoptosis to evaluate the effects of ANP on the gut barrier and its interplay with intestinal ANP and ROS. Rat small intestinal epithelial cells (IECs) were also treated with ANP and subjected to hypoxia/re-oxygenation injury, with or without PI3K/PLC inhibition, to elucidate the relationship between ANP/ROS signaling and PLC-γ1. Furthermore, we modulated PLC-γ1 expression in these IECs to examine its impact on ROS and ANP production. Results Intravenous ANP administration at 0.025 μg/kg/min during THS significantly increased intestinal ANP and ROS levels at 24 h. ANP treatment enhanced the expression of intestinal tight junction proteins and reduced IEC apoptosis. Inhibition of circulatory ROS diminished intestinal ANP levels, while suppression of circulatory ANP led to a reduction in intestinal ROS. Decreasing PLC-γ1 expression in hypoxia/re-oxygenation-treated IECs resulted in lower ROS and ANP levels, whereas augmenting PLC-γ1 expression did not alter these levels. Additionally, PI3K inhibition markedly decreased PLC-γ1 expression in these cells. Conclusion ANP-induced protection of the intestinal barrier in THS is mediated by an intrinsic PLC-γ1/ROS positive feedback loop. ANP preserves gut barrier integrity and reduces IEC apoptosis through this mechanism. Further studies are warranted to investigate the interaction between IECs and other cellular components within the PLC-γ1/ROS loop.

Qiliqiangxin capsule alleviates cardiac hypertrophy and cardiac dysfunction by regulating miR-382-5p/ATF3 axis

ObjectiveQiliqiangxin Capsule (QL) was investigated for its possible role in cardiac hypertrophy in this study. MethodsQL (0.5 mg/mL) was pre-treated in Neonatal Mouse Ventricular Cardiomyocytes (NMVCs) before induction of cardiomyocyte hypertrophy by Angiotensin II (Ang-II). Immunofluorescence staining for α-actinin was conducted to determine cell surface area. Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) of hypertrophy markers were examined. Ang-II infusion was given to stimulate cardiac hypertrophy in mice. The cardiac function of mice was detected by echocardiography, and the pathological status of myocardial tissue was observed. ResultsThe surface of cardiomyocytes was enlarged by Ang-II, and ANP and BNP levels were increased. QL processing could save these changes. miR-382-5p was upregulated in Ang-II-treated NMVCs, and reducing miR-382-5p could further enhance the therapeutic effect of QL while elevating miR-382-5p weakened the protective effect of QL. QL could inhibit miR-382-5p expression to negatively regulate Activated Transcription Factor 3 (ATF3) expression. Enhancing ATF3 expression rescued miR-382-5p upregulation-mediated role in NMVCs. In addition, QL alleviated Ang-II-stimulated cardiac hypertrophy and cardiac dysfunction in mice. ConclusionQL may alleviate cardiac hypertrophy and cardiac dysfunction via the miR-382-5p/ATF3 axis.

Pharmacological Research Progress of Novel Antihypertensive Drugs.

Cardiovascular disease stands as the leading cause of death globally, with hypertension emerging as an independent risk factor for its development. The worldwide prevalence of hypertension hovers around 30%, encompassing a staggering 1.2 billion patients, and continues to escalate annually. Medication plays a pivotal role in managing hypertension, not only effectively regulating blood pressure (BP) but also substantially mitigating the occurrence of cardiovascular and cerebrovascular diseases. This review comprehensively outlines the categories, mechanisms, clinical applications, and drawbacks of conventional antihypertensive drugs. It delves into the five primary pharmacological classifications, namely β-receptor blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and diuretics. The emphasis is placed on elucidating the mechanisms, advantages, and research progress of novel antihypertensive drugs targeting emerging areas. These include mineralocorticoid receptor antagonists (MRAs), atrial natriuretic peptides (ANPs), neutral endopeptidase inhibitors (NEPIs), sodium-dependent glucose transporter 2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) agonists, brain aminopeptidase A inhibitors (APAIs), and small interfering ribonucleic acids (siRNAs) targeting hepatic angiotensinogen. Compared to conventional antihypertensive drugs, these novel alternatives exhibit favorable antihypertensive effects with minimal adverse reactions. This review serves as a valuable reference for future research and the clinical application of antihypertensive drugs.

Evaluation of plasma atrial natriuretic peptide concentration in healthy bottlenose dolphins (Tursiops truncates).

There are currently no standard methods for diagnosing cardiac diseases in dolphins. These diseases may consequently be overlooked and go undiagnosed. The presence and severity of cardiac diseases in humans can be determined using blood tests. Atrial natriuretic peptide (ANP) used in human cardiac examinations has low species specificity. There have already been reports of homology between dolphin and human ANP; however, its potential for clinical application in dolphins has not been tested. This study was conducted to establish a reference for ANP levels in healthy bottlenose dolphins. Healthy bottlenose dolphins (seven females; estimated to be 7-30 years of age) at an aquarium in Japan were sampled. Each animal was tested for ANP at least three times, and the mean value and standard deviation were calculated to be 43.4 ± 19.2 pg/mL. In humans, patients with high plasma ANP levels have a poor prognosis. In veterinary medicine, cutoff values for the diagnosis of mitral regurgitation and heart failure in dogs have been established and used to predict prognosis. The results of the present study may contribute to the health management of bottlenose dolphins, particularly in the early detection and treatment of cardiac diseases.

Correlation of Atrial Natriuretic peptide (ANP) coding gene (NPPA) and Human Hypertension

Atrial natriuretic peptide (ANP) is a polypeptide hormone secreted by atrial muscle cells that has an endogenous antagonistic effect on the renin-angiotensin-aldosterone system (RAAS). It is believed to regulate salt and fluid balance and blood pressure. Blood samples (150) from males aged less than 20 to 55 years were collected from Al-Salam and Ibn-Sena Teaching Hospital in Mosul from 1/2/2022 to 1/9/2022. These samples, 5ml that include healthy and previously blood hypertension-diagnosed patients, were put into two tubes for hormonal and molecular study and divided into three classes: Control, which includes 50 samples from healthy individuals; hypertension without treatment patients 40 individuals and patients with treatment 60 individuals. Each class was divided into five groups according to their age. group (1) less than 20, group (2) 20-29, group (3) 30-39, group (4) 40-49 and group (5) 50-59 years. Serum ANP hormone concentration was measured, and the results revealed significant differences at between patients and healthy control groups. Hormone concentration had decreased in the 1,2 group while increased in groups 3,4,5 of treated and untreated patients compared with control groups with different group concentrations ranging from 28.86-23.16 pg/ml, indicating the effect of aging on hormone concentration. Also, the results revealed a different hormone concentration in untreated patient's groups that ranged between 12.97-28 pg./ml while the concentration of treated patient's groups ranged between 12.97-33.36 pg/ml, these differences in hormone concentration in all groups revealed the effect interference of aging and treatments that had a direct effect on the hormone concentration. Besides, the Amplicon copy numbers of the ANP coding gene (Nppa gene), considered an essential indicator of gene activities utilizing the real-time technique, showed a significant increase in patient groups, especially group (5) of both treated and untreated, compared with control. These results concluded that this hormone had an essential correlation with hypertension.

Knockdown of circSlc8a1 inhibited the ferroptosis in the angiotensin II treated H9c2 cells via miR-673-5p/TFRC axis.

This study aimed to investigate the role of circSlc8a1 in cardiac hypertrophy (CH), a pathological change in various cardiovascular diseases. An in vitro CH model was established using angiotensin II (AngII) treated H9c2 cells, followed by western blotting and RT-qPCR for detecting relative expressions. Cell viability and proliferation were analyzed using CCK-8 and EdU assays, while lactate dehydrogenase (LDH), reactive oxygen species (ROS), glutathione (GSH), and iron levels were determined using corresponding kits. Moreover, dual-luciferase reporter and RNA pull-down assays were performed to demonstrate whether miR-673-5p is bound to circSlc8a1 or transferrin receptor (TFRC). The results indicated that the expressions of circSlc8a1 and TFRC were increased, while miR-673-5p was decreased in the AngII treated H9c2 cells. The ferroptosis inhibitor treatment decreased the atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-major histocompatibility complex (β-MHC) protein expressions, and circSlc8a1 expressions. Knocking down of circSlc8a1 inhibited promoted the cell viability and proliferation, increased the GSH content, glutathione peroxidase 4, and solute carrier family 7 member 11 protein expressions, and decreased the LDH, ROS, iron levels, and RAS protein expressions. The MiR-673-5p inhibitor antagonized the role of si-circSlc8a1, and the over-expressed TFRC reversed the miR-673-5p mimicking effects in AngII treated H9c2 cells. CircSlc8a1 promoted the ferroptosis in CH via regulating the miR-673-5p/TFRC axis.

Retraction Note: Atrial natriuretic peptide protects against cisplatin‑induced granulocytopenia.

Retraction Note: Atrial natriuretic peptide protects against cisplatin‑induced granulocytopenia.

Integrated transcriptomics and metabolomics reveal the toxic mechanisms of mercury exposure to an endangered species Tachypleus tridentatus

Mercury (Hg) pollution is threatening the health of endangered Tachypleus tridentatus whereas the toxic mechanism is still unclear. This study combined transcriptomic and metabolomics technology to reveal the toxic mechanisms of mercury (Hg 2+, 0.025 mg/L) exposing to T. tridentatus larvae for 15 days. Mercury induced cellular toxicity and cardiovascular dysfunction by dysregulating the genes related to endocrine system, such as polyubiquitin-A, cathepsin B, atrial natriuretic peptide, etc. Mercury induced lipid metabolic disorder with the abnormal increase of lysoPC, leukotriene D4, and prostaglandin E2. Cytochrome P450 pathway was activated to produce anti-inflammatory substances to reconstruct the homeostasis. Mercury also inhibited arginine generation, which may affect the development of T. tridentatus by disrupting the crucial signaling pathway. The mercury methylation caused enhancement of S-adenosylmethionine to meet the need of methyl donor. The mechanisms described in present study provide new insight into the risk assessment of mercury exposure to T. tridentatus.

Atrial natriuretic peptide signaling co-regulates lipid metabolism and ventricular conduction system gene expression in the embryonic heart

It has been shown that atrial natriuretic peptide (ANP) and its high affinity receptor (NPRA) are involved in the formation of ventricular conduction system (VCS). Inherited genetic variants in fatty acid oxidation (FAO) genes are known to cause conduction abnormalities in newborn children. Although the effect of ANP on energy metabolism in noncardiac cell types is well documented, the role of lipid metabolism in VCS cell differentiation via ANP/NPRA signaling is not known. In this study, histological sections and primary cultures obtained from E11.5 mouse ventricles were analyzed to determine the role of metabolic adaptations in VCS cell fate determination and maturation. Exogenous treatment of E11.5 ventricular cells with ANP revealed a significant increase in lipid droplet accumulation, FAO and higher expression of VCS marker Cx40. Using specific inhibitors, we further identified PPARγ and FAO as critical downstream regulators of ANP-mediated regulation of metabolism and VCS formation.

A-Type Natriuretic Peptide Alters the Impact of Azithromycin on Planktonic Culture and on (Monospecies and Binary) Biofilms of Skin Bacteria Kytococcus schroeteri and Staphylococcus aureus.

It has been established that the human atrial natriuretic peptide is able to alter the effect of azithromycin on Kytococcus schroeteri H01 and Staphylococcus aureus 209P monospecies and binary biofilms. The effect of the hormone depends on the surface type and cultivation system, and it may have both enhancing and counteracting effects. The antagonistic effect of the hormone was observed mostly on hydrophobic surfaces, whereas the additive effect was observed on hydrophilic surfaces like glass. Also, the effect of the hormone depends on the antibiotic concentration and bacterial species. The combination of azithromycin and ANP led to an amplification of cell aggregation in biofilms, to the potential increase in matrix synthesis, and to a decrease in S. aureus in the binary community. Also, ANP, azithromycin, and their combinations caused the differential expression of genes of resistance to different antibiotics, like macrolides (mostly increasing expression in kytococci), fluoroquinolones, aminoglycosides, and others, in both bacteria.

Unveiling the Therapeutic Potential of SGLT2 inhibitors and Oral Ketone Ester in Heart Failure with Preserved Ejection Fraction: A Comprehensive Exploration of Cardiac Function, Structure, and Metabolism in a Rat Model

BackgroundThis study investigated the potential efficacy of SGLT2 inhibitors empagliflozin and oral ketone supplementation as treatments for heart failure with preserved ejection fraction (HFpEF), which is often associated with obesity and type 2 diabetes mellitus. Methods20-week-old obese ZSF-1 rats were given different treatments for 12 weeks, including vehicle, empagliflozin, ketone ester (KE), or a combination of empagliflozin and KE. Cardiac magnetic resonance imaging (CMR) and hyperpolarized carbon-13 (13C) labeled pyruvate magnetic resonance spectroscopy imaging were used to evaluate cardiac function and metabolism, while histological and molecular markers of cardiac remodeling were assessed in the left ventricle. ResultsThe untreated HFpEF rats exhibited obesity, diabetes, cardiac hypertrophy, atrial enlargement, lung congestion, and increased cardiomyocyte size and cardiac expression of atrial natriuretic peptide (ANP) and fibrosis marker col1a1 and TIMP1. The treatment groups exhibited decreased body weight, increased circulating ketone levels, and reduced blood glucose levels. All treatment regimens significantly attenuated ventricular hypertrophy, atrial enlargement, and lung congestion. Furthermore, all treatments significantly reduced cardiomyocyte size and the expression of ANP and fibrosis marker. The combination of empagliflozin and KE showed the greatest improvement in diastolic function and cardiac ATP levels. Interestingly, hyperpolarized [1-13C] pyruvate detected a decrease in lactate/pyruvate ratio in the hearts treated with empagliflozin. ConclusionObese ZSF1 rats exhibit features of clinical HFpEF with predominant background of obesity and diabetes. A combination of empagliflozin and KE has greater benefits in treating HFpEF. Targeting cardiometabolic dysregulation may be a promising approach for HFpEF treatment.

Enhanced central sympathetic tone induces heart failure with preserved ejection fraction (HFpEF) in rats.

Heart failure with preserved ejection fraction (HFpEF) is a heterogenous clinical syndrome characterized by diastolic dysfunction, concentric cardiac left ventricular (LV) hypertrophy, and myocardial fibrosis with preserved systolic function. However, the underlying mechanisms of HFpEF are not clear. We hypothesize that an enhanced central sympathetic drive is sufficient to induce LV dysfunction and HFpEF in rats. Male Sprague-Dawley rats were subjected to central infusion of either saline controls (saline) or angiotensin II (Ang II, 20ng/min, i.c.v) via osmotic mini-pumps for 14 days to elicit enhanced sympathetic drive. Echocardiography and invasive cardiac catheterization were used to measure systolic and diastolic functions. Mean arterial pressure, heart rate, left ventricular end-diastolic pressure (LVEDP), and ± dP/dt changes in responses to isoproterenol (0.5μg/kg, iv) were measured. Central infusion of Ang II resulted in increased sympatho-excitation with a consequent increase in blood pressure. Although the ejection fraction was comparable between the groups, there was a decrease in the E/A ratio (saline: 1.5 ± 0.2 vs Ang II: 1.2 ± 0.1). LVEDP was significantly increased in the Ang II-treated group (saline: 1.8 ± 0.2 vs Ang II: 4.6 ± 0.5). The increase in +dP/dt to isoproterenol was not significantly different between the groups, but the response in -dP/dt was significantly lower in Ang II-infused rats (saline: 11,765 ± 708mmHg/s vs Ang II: 8,581 ± 661). Ang II-infused rats demonstrated an increased heart to body weight ratio, cardiomyocyte hypertrophy, and fibrosis. There were elevated levels of atrial natriuretic peptide and interleukin-6 in the Ang II-infused group. In conclusion, central infusion of Ang II in rats induces sympatho-excitation with concurrent diastolic dysfunction, pathological cardiac concentric hypertrophy, and cardiac fibrosis. This novel model of centrally mediated sympatho-excitation demonstrates characteristic diastolic dysfunction in rats, representing a potentially useful preclinical murine model of HFpEF to investigate various altered underlying mechanisms during HFpEF in future studies.

Effects of Long-Term Administration of Bovine Bone Gelatin Peptides on Myocardial Hypertrophy in Spontaneously Hypertensive Rats.

The research purpose was to investigate the effects and the underlying molecular mechanisms of bovine bone gelatin peptides (BGP) on myocardial hypertrophy in spontaneously hypertensive rats (SHR). BGP relieved myocardial hypertrophy and fibrosis in SHR rats in a dose-dependent manner by reducing the left ventricular mass index, myocardial cell diameter, myocardial fibrosis area, and levels of myocardial hypertrophy markers (atrial natriuretic and brain natriuretic peptide). Label-free quantitative proteomics analysis showed that long-term administration of BGP changed the left ventricle proteomes of SHR. The 37 differentially expressed proteins in the high-dose BGP group participated in multiple signaling pathways associated with cardiac hypertrophy and fibrosis indicating that BGP could play a cardioprotective effect on SHR rats by targeting multiple signaling pathways. Further validation experiments showed that a high dose of BGP inhibited the expression of phosphoinositide 3-kinase (Pi3k), phosphorylated protein kinase B (p-Akt), and transforming growth factor-beta 1 (TGF-β1) in the myocardial tissue of SHR rats. Together, BGP could be an effective candidate for functional nutritional supplements to inhibit myocardial hypertrophy and fibrosis by negatively regulating the TGF-β1 and Pi3k/Akt signaling pathways.

Transcriptional cofactor dyxin mediates hypertrophic response in the heart during angiotensin II-induced hypertension.

Dyxin is a LIM-domain containing transcriptional regulator protein shown to play a role in a hypertrophic response in the heart. Here, the effect of adenoviral dyxin overexpression was studied on cardiac function and gene expression in the normal heart and in angiotensin II (Ang II)-induced hypertension in rats. The adenovirus-mediated intramyocardial gene transfer of dyxin (1.5x109 infectious units/animal) was performed into the left ventricle (LV) of Sprague-Dawley rats with and without the Ang II (33 μg/kg/h) infusion, administered via osmotic minipumps for 1 and 2 weeks. Echocardiography was used to assess the structural and functional changes. Dyxin expression and localization in the heart was analyzed with quantitative RT-PCR and immunohistochemistry, respectively. In the normal rat heart, the adenoviral overexpression of dyxin did not alter LV function in normal hearts as assessed by echocardiography. Dyxin was found to be localized in the cardiomyocytes as shown by the immunohistochemical staining. In Ang II-induced hypertrophy, echocardiographic data revealed a significant increase in the posterior wall diameter both in systole (21%, P<0.05) and diastole (21%, P<0.01) as well as in the diameter of the interventricular septum in systole (19%, P<0.05) in the dyxin-injected group compared with the LacZ-injected animals after two weeks of Ang II infusion. Interestingly, a significant decrease in the levels of both atrial natriuretic peptide (ANP) mRNA (55%, P<0.01) and B-type natriuretic peptide (BNP) mRNA (68%, P<0.05) was observed in the dyxin-injected group compared with the LacZ control group after one week of Ang II infusion. These results indicate that dyxin overexpression was deteriorative against pressure overload by inducing structural changes in the LV in rats. Interestingly, simultaneous adenoviral overexpression of dyxin suppressed the Ang II-induced changes of ANP and BNP genes suggesting that dyxin might have a role as a regulator of the cardiac hypertrophic gene program.

Inhibition of the STIM1/Orai1 Signaling Pathway by Glycine Betaine Mitigates Myocardial Hypertrophy in Spontaneous Hypertension Rats.

Spontaneous hypertension is a leading risk factor for cardiovascular diseases morbidity and mortality. Glycine betaine (GB) is a natural vitamin that has the potential to lower blood pressure. This work attempted to investigate the role and mechanisms of GB in spontaneous hypertension. Spontaneously hypertensive rats (SHRs) were administrated with 100, 200, or 400 mg/kg of GB by gavage or combined with by injection of lentivirus-mediated STIM1 overexpression vector. The heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart weight/body weight (HW/BW) of rats were monitored. The pathological changes in myocardium were examined by hematoxylin and eosin staining and Masson staining. The expression of genes and proteins was detected by quantitative real-time PCR, western blotting, and immunohistochemistry. GB at 200 and 400 mg/kg reduced the HR, SBP, DBP and HW/BW in SHRs. GB decreased the cross-sectional area and fibrotic area in the myocardium and downregulated the expression of atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC) in the myocardium of SHRs. It indicated that GB treatment effectively alleviated myocardial hypertrophy in SHRs. Additionally, GB treatment repressed the expression of stromal interaction molecule 1 (STIM1) and calcium release-activated calcium channel protein 1 (Orai1) in the myocardium of SHRs. STIM1 overexpression reversed GB treatment-mediated inhibition of myocardial hypertrophy in SHRs. In conclusion, GB repressed STIM1/Orai1 signaling pathway, which contributed to alleviating myocardial hypertrophy in SHRs. Thus, our study provides a theoretical basis for GB as an antihypertensive drug.

Follistatin-like 1 is a myokine regulating lipid mobilization during endurance exercise and recovery.

The aim of this study was to investigate the role of the follistatin-like 1 (Fstl1) and disco-interacting protein 2 homolog A (DIP2a) axis in relation to lipid metabolism during and after endurance exercise and to elucidate the mechanisms underlying the metabolic effects of Fstl1 on adipocytes, considering its regulation by exercise and muscle mass and its link to obesity. Twenty-nine sedentary males participated in endurance exercise, and blood samples were collected during and after the exercise. Body composition, Fstl1, glycerol, epinephrine, growth hormone, and atrial natriuretic peptide were measured. 3T3-L1 adipocytes, with or without DIP2a knockdown, were treated with Fstl1 to assess glycerol release, cyclic AMP/cyclic GMP production, and hormone sensitive lipase phosphorylation. The association between DIP2a gene expression levels in human adipose tissues and exercise-induced lipolysis was examined. Fstl1 levels significantly increased during endurance exercise and following recovery, correlating with lean body mass and lipolysis. In 3T3-L1 adipocytes, Fstl1 increased glycerol release, cyclic GMP production, and hormone sensitive lipase activation, but these effects were attenuated by DIP2a knockdown. DIP2a gene expression in human adipose tissues correlated with serum glycerol concentrations during endurance exercise. Fstl1 is a myokine facilitating lipid mobilization during and after endurance exercise through DIP2a-mediated lipolytic effects in adipocytes.

Unveiling the potential role of natriuretic peptide receptor a isoforms in fine-tuning the cGMP production and tissue-specific function

Atrial natriuretic peptide (ANP) is a peptide hormone that regulates blood pressure and volume. ANP interacts with natriuretic peptide receptor-A (NPR-A) to lower the blood pressure through vasodilation, diuresis and natriuresis. Previously, we designed two human ANP analogues, one with exclusively diuretic function (DGD-ANP) and the other with exclusively vasodilatory function (DRD-ANP). Although both ANP analogues interact with NPR-A, their ability to produce cGMP was different. Three alternatively spliced isoforms of NPR-A were previously identified in rodents. Here, we evaluated the putative human isoforms for their cGMP production independently and in combination with WT NPR-A in various percentages. All three NPR-A isoforms failed to produce cGMP in the presence of ANP, DGD-ANP, or DRD-ANP. Co-expression of isoforms with WT NPR-A were found to significantly impair cGMP production. Considering the differential tissue expression levels of all three spliced isoforms in rodents have previously been demonstrated, the existence of these non-functional receptor isoforms may act as negative regulator for ANP/NPR-A activation and fine-tune cGMP production by WT NPR-A to different degree in different tissues. Thus, NPR-A isoforms potentially contribute to tissue-specific functions of ANP.