Estrogen deficiency is a major risk factor for postmenopausal hypertension. PDZK1, an estrogen-responsive scaffold protein, may interact with the β2-adrenergic receptor (β2-AR) to regulate vascular function, but this axis has not been characterized in the context of estrogen-deficient hypertension. We used ovariectomized and PDZK1 knockout mice infused with angiotensin II to model hypertension in vivo, and HUVECs for mechanistic studies in vitro. Techniques included hemodynamic measurements, histology, molecular interaction assay, chromatin immunoprecipitation, and functional cellular assays. Ovariectomy exacerbated Ang II-induced hypertension and vascular remodeling, which correlated with reduced PDZK1 expression. PDZK1 KO mice showed enhanced hypertensive responses and impaired endothelium-dependent relaxation. Mechanistically, PDZK1 interacted with β2-AR via its PDZ1 and PDZ4 domains, stabilizing β2-AR and activating the downstream ERK1/2/c-Fos pathway to promote endothelial proliferation. PDZK1 knockdown or β2-AR inhibition attenuated this signaling and suppressed endothelial repair. Our study identifies a novel PDZK1/β2-AR/ERK1/2/c-Fos axis that is essential for maintaining endothelial function under estrogen-sufficient conditions. Disruption of this pathway in the context of estrogen deficiency contributes to hypertension, highlighting PDZK1 as a potential therapeutic target for postmenopausal hypertension.

Diabetes, a systemic metabolic disorder, often involves multi-organ interactions in its complications. Although the pathogenesis of diabetic cardiomyopathy (DCM) is complex, the role of the liver in this process remains unclear. Using the db/db mouse model, this study demonstrated that metabolic dysfunction associated steatotic liver disease (MASLD) reduced hepatic synthesis of hemopexin (HPX) and impaired Kupffer cell function, leading to systemic heme accumulation. This circulating heme was taken up by cardiomyocytes via the membrane protein feline leukemia virus subgroup C receptor 2 (FLVCR2), which induced cardiomyocyte pyroptosis and aggravated myocardial injury. Intervention experiments indicated that targeted supplementation of hepatic HPX effectively restored heme homeostasis, reduced exogenous heme influx into cardiomyocytes, and improved cardiac function. These findings reveal a liver–heart axis mechanism in which hepatic heme mediates cardiomyocyte pyroptosis through FLVCR2, offering novel perspectives for the prevention and treatment of DCM.

Hypertension is a chronic disease accompanied by vascular remodeling. As an m6A demethylase, ALKBH5 is implicated in cardiovascular diseases. Herein, we demonstrated that ALKBH5 expression was upregulated in the aortic tissues of spontaneously hypertensive rats (SHR), with predominant localization in vascular smooth muscle cells (VSMCs). To define ALKBH5 function, we generated an SM22α-driven, VSMC-specific Alkbh5-knockdown AAV9 vector and administered a single tail-vein injection (11 × 10¹² v.g./rat) to 4-week-old male SHRs. Alkbh5 knockdown markedly lowered arterial pressure in SHRs, ameliorated left ventricular remodeling, attenuated aortic media thickening and extracellular matrix deposition, and suppressed the contractile-to-synthetic/proliferative phenotypic switch of VSMCs. Primary thoracic aortic VSMCs were isolated from 16-week-old SHRs and Wistar-Kyoto (WKY) rats, with Alkbh5 knockdown achieved via adenoviral transduction. Separately, primary human aortic smooth muscle cells were pretreated with 1 μM angiotensin II for 24 h prior to adenoviral infection. In vitro assays further verified that ALKBH5 knockdown suppressed proliferation and the contractile-to-synthetic/proliferative phenotypic switch in VSMCs in hypertensive context. Subsequent mechanistic studies revealed that ALKBH5 knockdown enhanced the stability of TEAD3 mRNA by increasing its m6A modification; the upregulated TEAD3 could directly bind to the PDZK1 promoter and promote its transcription. Moreover, PDZK1 knockdown reversed the inhibitory effect of ALKBH5 knockdown on the abnormal proliferation of VSMCs. In conclusion, ALKBH5 knockdown inhibits the abnormal phenotypic switch of VSMCs through the TEAD3/PDZK1 axis, thereby alleviating vascular remodeling caused by hypertension. These findings suggest that ALKBH5 may serve as a potential therapeutic target for hypertension.

Myocardial infarction (MI) remains a leading cardiovascular cause of mortality in patients, primarily driven by adverse post-MI ventricular remodeling tightly linked to inflammation. Finerenone, the first non-steroidal mineralocorticoid receptor (MR) antagonist, is clinically indicated to improve cardiovascular and renal outcomes in patients with chronic kidney disease (CKD) associated with type 2 Diabetes Mellitus (T2DM). Multiple previous studies have validated the robust cardioprotective effects of finerenone post MI. Nevertheless, whether finerenone ameliorates post-MI ventricular remodeling by regulating pyroptosis, an inflammation-associated programmed cell death, and its specific underlying molecular mechanisms remain largely uncharacterized. Male Sprague-Dawley (SD) rats were randomly divided into Sham group, MI group, MI + Spironolactone group and MI + Finerenone group. Compared with MI group, finerenone ameliorated ventricular remodeling and inhibited inflammatory cell infiltration post MI in rats. Meanwhile, finerenone reduced myocardial MR expression, pyroptosis and activation of NF-κB signaling pathway post MI in rats. The in vitro experimental results further showed finerenone could inhibit pyroptosis through MR-activated NF-κB pathway. Finerenone could reduce cardiac inflammation and improve ventricular remodeling post MI probably by decreasing NF-κB signaling pathway mediated pyroptosis via MR, which offer promising a novel therapeutic target for clinical intervention in patients with MI.

Research indicates that patients with salt-sensitive (SS) hypertension experience higher morbidity and target organ damage than in patients with non-SS hypertension. Dysregulated macrophage activation has been implicated in SS hypertension development, with lysine acetylation playing a role in modulating macrophage function. However, the role of macrophage acetylation patterns in SS hypertension remains unclear. This study aimed to investigate how acetylation regulates macrophage function and its role in the pathogenesis of SS hypertension. We employed quantitative acetylation proteomics to characterize the acetylome of bone marrow-derived macrophages in Dahl SS hypertensive rats fed either a high-salt or a low-salt diet. We identified 94 hyperacetylated and 49 hypoacetylated sites on 79 and 45 proteins, respectively, in the high-salt group. Notably, acetylation levels increased at lysine 20 (K20) and K46 on histone H2B, at K56 on H3, and at K77 and K79 on H4c2. We also identified conserved acetylation motifs, analyzed their Gene Ontology terms and pathways, and explored the protein–protein interactions of these differentially acetylated proteins using bioinformatics analyses. Finally, we validated the altered acetylation of H2, H3, H4, and several metabolic proteins using immunoprecipitation and western blotting. Overall, these findings offer insights into the role of lysine acetylation in macrophages from SS hypertensive rats, revealing potential therapeutic targets. Our analysis showed a landscape of lysine acetylation in bone marrow-derived macrophages (BMDMs) from salt-sensitive rats. Furthermore, we clearly identified significantly altered acetylated sites in low-salt and high-salt groups and validated the altered acetylation levels of several histones and metabolic proteins. IP, immunoprecipitation; TMT, tandem mass tag; LC–MS, liquid chromatography-mass spectrometry; HPLC, high-performance liquid chromatography.

Hypertension is a risk factor for cardiovascular diseases, primarily through its induction of pathological vascular and ventricular remodeling. TEA domain transcription factor 3 (TEAD3) is a transcription factor highly expressed in myocardial tissues. PDZ domain-containing 1 (PDZK1) has been reported to protect blood vessels. This study discovered decreased expression of TEAD3 and PDZK1 in the aortic tissues of spontaneously hypertensive rats (SHRs). TEAD3 overexpression in SHR vascular smooth muscle cells (VSMCs) driven by the SM22α promoter was achieved through adeno-associated virus delivery. TEAD3 overexpression alleviated aortic remodeling by reducing elastic fiber and collagen deposition. This improvement in vascular structure attenuated hypertension. Subsequently, ventricular remodeling was alleviated by reducing periaortic myocardial fibrosis and left ventricular posterior wall thickness. To elucidate the underlying mechanisms, we overexpressed TEAD3 or PDZK1 in SHR-derived VSMCs via adenoviral infection. Both interventions suppressed VSMC proliferation and migration. Crucially, TEAD3 overexpression upregulated PDZK1 expression, and DNA pull-down assays confirmed direct binding of TEAD3 protein to the PDZK1 promoter. PDZK1 knockdown abolished the anti-proliferative and anti-migratory effects of TEAD3. Further analysis suggested that PDZK1 exerted its protective role by inhibiting the phosphoinositide-3-kinase adaptor protein 1-mediated PI3K/Akt pathway. In conclusion, this study reveals that TEAD3-PDZK1 axis attenuates the abnormal proliferation and migration of VSMCs, which ameliorates aortic and left ventricular remodeling in hypertensive conditions. These findings establish a molecular basis for developing targeted therapies against hypertension-induced cardiovascular remodeling.

BACKGROUND AND PURPOSE:Myocardial fibrosis is a key pathological feature of hypertension, closely associated with mitochondrial dysfunction and calcium overload. The calcium-sensing receptor (CaSR) has emerged as a potential mediator in this process, but its mechanistic role remains unclear. This study aimed to investigate whether Calhex231, a selective CaSR antagonist, could attenuate myocardial fibrosis in Dahl salt-sensitive (SS) rats by restoring mitochondrial dynamics and intracellular calcium homeostasis. METHODS:Hypertension was induced in Dahl SS rats using an 8% NaCl diet. From week 5, rats were treated with Calhex231 (10 μmol/kg/day) for 6 weeks. In vitro, cardiac fibroblasts (CFs) were stimulated with TGF-β1 (10 ng/ml) and treated with either Calhex231 or Mdivi-1 (a Drp1 inhibitor). Assessments included echocardiography, histological staining (Masson, HE), immunohistochemistry, Western blotting, and fluorescence-based analyses of mitochondrial membrane potential (JC-1), oxidative stress (Dihydroethidium, SOD1/2), intracellular Ca2+ (Fluo-4 AM), and fibrosis markers (α-SMA, Collagen I/III, MMP-2/9). RESULTS:Calhex231 significantly reduced blood pressure and myocardial fibrosis in hypertensive rats, accompanied by improved cardiac structure and diastolic function. Mechanistically, Calhex231 suppressed mitochondrial fission proteins (Drp1, Fis1) and upregulated fusion proteins (MFN2, OPA1), restoring mitochondrial homeostasis. In TGF-β1-stimulated CFs, Calhex231 alleviated calcium overload, preserved mitochondrial membrane potential, reduced ROS production, and downregulated fibrotic markers. Similar protective effects were observed with Mdivi-1, highlighting the involvement of Drp1-mediated fission in CaSR-induced fibrosis. CONCLUSION:Inhibition of CaSR with Calhex231 exerts cardioprotective effects by suppressing Drp1-dependent mitochondrial fission, thereby mitigating oxidative stress and calcium overload. These findings support CaSR as a promising therapeutic target for myocardial fibrosis in salt-sensitive hypertension.

In this study, we found that PDZK1, a scaffold protein, interacts with the β₂-adrenergic receptor (ADRB2) through its PDZ domains, stabilising ADRB2 by inhibiting its ubiquitination and proteasomal degradation. This study explored the PDZK1-ADRB2 interaction and its role in hypertension-induced vascular remodelling. Using PDZK1 knockout mice infused with angiotensin II, we found that PDZK1 deficiency further exacerbates angiotensin II-induced hypertension, vascular dysfunction, and vascular remodelling. Mechanistically, PDZK1 stabilises ADRB2 protein by preventing its ubiquitination and proteasomal degradation, thereby maintaining ADRB2-mediated vasodilation. Additionally, PDZK1 prevents ADRB2 internalisation and its interaction with β-arrestin, thereby inhibiting β-arrestin-mediated ERK activation and suppressing vascular smooth muscle cell (VSMC) phenotypic switching. This mechanism contributes to vascular protection under hypertensive conditions. Targeting the PDZK1/ADRB2 interaction may provide a novel therapeutic strategy for hypertension-related vascular complications.

Introduction Hyperglycemia-induced endothelial cell injury is one of the main causes of diabetic vasculopathy. Fat mass and obesity-associated protein (FTO) was the first RNA N6-methyladenosine (m6A) demethylase identified; it participates in the pathogenesis of diabetes. However, the role of FTO in hyperglycemia-induced vascular endothelial cell injury remains unclear. Materials and methods The effects of FTO on cellular m6A, autophagy, oxidative stress, proliferation, and cytotoxicity were explored in human umbilical vein endothelial cells (HUVECs) treated with high glucose (33.3 mmol/mL) after overexpression or pharmacological inhibition of FTO. MeRIP-qPCR and RNA stability assays were used to explore the molecular mechanisms by which FTO regulates autophagy. Results High glucose treatment increased m6A levels and reduced FTO protein expression in HUVECs. Wild-type overexpression of FTO markedly inhibited reactive oxygen species generation by promoting autophagy, increasing endothelial cell proliferation, and decreasing the cytotoxicity of high glucose concentrations. The pharmacological inhibition of FTO showed the opposite results. Mechanistically, we identified Unc-51-like kinase 1 (ULK1), a gene responsible for autophagosome formation, as a downstream target of FTO-mediated m6A modification. FTO overexpression demethylated ULK1 mRNA and inhibited its degradation in an m6A-YTHDF2-dependent manner, leading to autophagy activation. Conclusions Our study demonstrates the functional importance of FTO-mediated m6A modification in alleviating endothelial cell injury under high glucose conditions and indicates that FTO may be a novel therapeutic target for diabetic vascular complications.

Background Cardiomyocyte apoptosis plays an important role in alcoholic cardiac injury. However, the association between calcium-sensing receptor (CaSR) and alcohol-induced cardiomyocyte apoptosis remain unclear. Therefore, we investigated the role and its moleculer mechanism of CaSR in rat cardiomyocyte apoptosis induced by alcohol. Methods Alcohol-induced cardiomyocyte apoptosis in vivo and in vitro model of rats were applied in this study. The expression of CaSR, endoplasmic reticulum stress markers and apoptosis were tested by immunohistological staining, western blot, TUNEL and flow cytometry, respectively. [Ca 2+ ] i were detected by confocal laser scanning microscopy. Results Compared with the control group, alcohol intake (AI) led to abnormal arrangements of cardiomyocytes and obvious increase of myocardial apoptosis. Moreover, AI also significantly upregulated protein expression of CaSR, GRP94, caspase-12 and CHOP. Alcohol induced apoptosis of cultured cardiomyocytes of rats in a dose-dependent way. Activation of CaSR markedly enhanced cardiomyocyte apoptosis and ERS induced by alcohol, ERS inducer also significantly increased cardiomyocyte apoptosis without activating CaSR. Furthermore, GdCl 3 augmented alcohol-induced increase of [Ca 2+ ] i in cardiomyocytes, which was attenuated by NPS2390 but not 4-PBA pre-treatment. Conclusions Alcohol could induce cardiomyocyte apoptosis in rats in vivo and in vitro, which was mediated probably via activating CaSR, and then ERS and the increase of the cytosolic [Ca 2+ ] i . This provides a potential target for preventing cardiomyocyte apoptosis and cardiomyopathy induced by alochol.

Background: The aim of this study was to investigate whether calcium-sensing receptor (CaSR) was involved in HRF-mediated exacerbation of MI/R injury through NLRP3 inflammasome activation and pyroptosis. Methods: In vivo, a rat MI/R model was established by ligating the left coronary artery, and short-term HRF exposure was induced during reoxygenation. Then, TUNEL, H&E, Masson staining, immunohistochemical (IHC) and serum levels of lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK), as well as the expression levels of CaSR and pyroptosis-related proteins in heart tissues, were measured. H9c2 cells were cultured to create a hypoxia/reoxygenation (H/R) model and exposed to different concentrations of RF. After pretreatment with the CaSR activator gadolinium chloride (GdCl3) and inhibitor NPS2143 in the H/R model and treatment with HRF, we compared cellular viability, TUNEL, cytosolic [Ca2+]i, the levels of LDH and CK, pyroptosis-related proteins and CaSR in H9c2 cells. We further researched the mechanisms of CaSR-mediated pyroptosis in the H/R+HRF model by CaSR-shRNA, Ac-YVAD-CMK, MCC950 and NAC. Results: We found that HRF significantly increased CaSR expression, rate of cell death, levels of CK and LDH, and exacerbated pyroptosis in MI/R model. In vitro, HRF increased CaSR expression, decreased viability, enhanced cytosolic [Ca2+]i and exacerbated pyroptosis in H/R cells. Pretreated with GdCl3 worsen these changes, and NPS2143, MCC950, Ac-YVAD-CMK, NAC and sh-CaSR can reversed these effects. Conclusion: Exposure to HRF for a short time exacerbates MI/R-induced injury by targeting CaSR to increase cytosolic [Ca2+]i and ROS levels, which mediate the NLRP3 inflammasome and pyroptosis.

Ventricular remodeling is one of the main causes of mortality from heart failure due to hypertension. Exploring its mechanism and finding therapeutic targets have become urgent scientific problems to be solved. A number of studies have shown that Mas, as an Ang-(1-7) specific receptor, was significantly reduced in myocardial tissue of rats undergoing hypertensive ventricular remodeling. It has been reported that Mas receptor levels are significantly downregulated in myocardium undergoing ventricular remodeling, but studies focused on intracellular and post-translational modifications of Mas are lacking. The results of this research are as follows: (1) PDZK1 interacts with the carboxyl terminus of Mas through its PDZ1 domain; (2) the expression of PDZK1 and Mas is decreased in rats undergoing hypertensive ventricular remodeling, and PDZK1 upregulation can ameliorate hypertensive myocardial fibrosis and myocardial hypertrophy; (3) PDZK1 enhances the stability of Mas protein through the proteasome pathway, and the proteasome inhibitor MG132 promotes hypertensive ventricular remodeling. PDZK1 improves ventricular remodeling in hypertensive rats by regulating Mas receptor stability. This study provides a scientific basis for the prevention and treatment of ventricular remodeling.

MicroRNAs (miRNAs) are noncoding RNAs that play an important role in the mechanisms of diabetic cardiomyopathy (DCM); however, whether human recombinant relaxin-3 (H3 relaxin) inhibits myocardial injury in DCM rats and the underlying mechanisms involving miRNAs remain unknown. miRNA expression profiles were detected using miRNA microarray and bioinformatics analyses of myocardial tissues from control, DCM, and H3 relaxin-administered DCM groups, and the regulatory mechanisms of the miRNAs were investigated. A total of 5 miRNAs were downregulated in the myocardial tissues of DCM rats and upregulated in H3 relaxin-treated DCM rats, and 1 miRNA (miRNA let-7d-3p) was increased in the myocardial tissue of DCM rats and decreased in H3 relaxin-treated DCM rats as revealed by miRNA microarray and validated by real-time polymerase chain reaction. Important signaling pathways were found to be triggered by the differentially expressed miRNAs, including metabolism, cancer, Rap1, PI3K-Akt, and MAPK signaling pathways. The study revealed that H3 relaxin improved glucose uptake in DCM rats, potentially via the regulation of miRNA let-7d-3p.

目的 调查哈尔滨市老年慢性心力衰竭(CHF)患者自我管理水平现状,探讨其与自我效能的相关性.方法 采用随机分层抽样抽取2018年1月 ～2018年6月哈尔滨市7个区12个医院CHF患者560例.均行心力衰竭自我管理量表、自我效能量表评估;Pearson相关分析患者自我管理水平与自我效能的相关性.结果 患者总体自我管理水平得分率为64.96％,其中药物管理、 饮食管理得分率较高(69.85％、67.92％),心理和社会适应管理得分率居中(63.65％),症状管理得分率较低(61.14％);在不同病程、文化程度、居住情况、人均月收入、自理能力、NYHA心功能分级及是否合并抑郁状态方面,CHF患者总体自我管理水平比较差异均有统计学意义(P<0.05);自我效能总分为(36.34±5.17)分,得分率为60.57％,自我效能良好125例(22.32％),一般319例(56.96％),差116例(20.72％);Pearson相关分析结果显示,560例CHF患者自我管理各维度及总体自我管理评分与自我效能各维度及总体自我效能评分均呈正相关.结论 哈尔滨市老年慢性心力衰竭患者自我管理、 自我效能水平均处于中等水平,二者呈正相关.可通过综合干预来增强患者自我效能,提高自我管理水平.

目的 探究慢性稳定性冠心病(SCAD)患者血浆解偶联蛋白-2(UCP-2)表达水平及临床意义.方法 选取2017年1月～2018年12月哈尔滨医科大学附属第一医院心内科住院的SCAD患者216例为SCAD组,同期住院的非SCAD患者196例为对照组.SCAD组均行冠状动脉造影,记录Gensini评分及罪犯血管支数;检测两组血浆UCP-2、氨基末端B型脑利钠肽前体(NT-proBNP)水平;Spearman法分析血浆UCP-2与NT-proBNP及Gensini评分的相关性,ROC曲线法分析UCP-2及NT-proBNP诊断SCAD的价值.结果 SCAD组UCP-2、NT-proBNP水平高于对照组(P<0.05);Gensini评分低、中、高患者血浆UCP-2、NT-proBNP水平逐渐升高(P<0.05);单支病变、双支病变、多支病变患者血浆UCP-2、NT-proBNP水平逐渐升高(P<0.05);Pearson相关分析显示,血浆UCP-2、NT-proBNP与Gensini评分均呈明显正相关(P<0.05);血浆UCP-2诊断SCAD的AUC、灵敏度、特异度与NT-proBNP比较差异均无统计学意义(P>0.05).结论 SCAD患者血浆UCP-2上调,且升高幅度与冠状动脉狭窄程度呈正相关,可作为SCAD诊断的分子标志物.

Chemokines may promote the formation and instability of atherosclerotic plaque, which is the most common cause of acute coronary syndrome. The aim of this study was to clarify the function of monocyte chemotactic protein-3 (MCP-3) in the stability of atherosclerotic plaque, to determine the role of tissue factor pathway inhibitor (TFPI) on the development and stability of atherosclerotic plaques, and to further elucidate the anti-atherosclerotic mechanism of TFPI with the emphasis on chemokine MCP-3. We constructed an adenovirus-mediated shRNA against mouse MCP-3 (Ad-MCP-3-shRNA) and an adenovirus-containing TFPI (Ad-TFPI), and tranferred them in a model of vulnerable plaque in ApoE-/- mice respectively. Here, we reported that MCP-3-shRNA and TFPI could both reduce the plaque area and decrease the content of lipids and macrophages, on the contrary, the fibrous cap thickness and content of collagen and smooth muscle cells were increased. In addition, the expression of MCP-3 and CC chemokine receptor 2 (CCR2) was decreased by TFPI transfer. These data provide the first in vivo evidence that MCP-3 is a major contributor to the unstability of atherosclerotic plaque and TFPI may exert its anti-atherosclerotic effects and promote stabilisation of plaque at least partly through inhibiting MCP-3/CCR2 pathway, which may be a new therapeutic method for atherosclerosis.

Human recombinant relaxin-3 (H3 relaxin ),a small molecule peptide hormone, ameliorated myocardial injury after myocardial infarction or isoprenaline injection by inhibiting apoptosis and fibrosis. However, whether H3 relaxin protects vascular function in rats with type 1 diabetes and its mechanism are unknown. In type 1 diabetes rats model induced by streptozotocin (STZ), rats were subcutaneously injected H3 relaxin (2 µg/kg/d or 0.2 µg/kg/d) for 2 weeks. At 4 or 8 weeks after STZ injection, we detected the expression of fibrosis (type I and III collagen), ERS (endoplasmic reticulum stress) and NLRP3 inflammasome activation in the aortas and inflammation markers in the plasma from rats with diabetes. Compared with the diabetic rats, H3 relaxin treatment exhibited markedly decreased plasma oxidative stress markers (TNF-a and MDA) levels. The protein expression levels of type I and III collagen in the aortas were increased in rats with diabetes, inhibited by H3 relaxin. H3 relaxin treatment inhibited ERS (GRP78 and CHOP) and NLRP3 inflammasome activation in the aortas of diabetic rats. These results suggest that H3 relaxin inhibited fibrosis, ERS and inflammation activation in the aortas of type 1 diabetic rats.

The calcium‐sensing receptor (CaSR) is involved in the pathophysiology of many cardiovascular diseases, including myocardial infarction (MI) and hypertension. The role of Calhex231, a specific inhibitor of CaSR, in myocardial fibrosis following MI is still unclear. Using Wistar rats, we investigated whether Calhex231 ameliorates myocardial fibrosis through the autophagy‐NLRP3 inflammasome pathway in macrophages post myocardial infarction (MI). The rats were randomly divided into sham, MI and MI + Calhex231 groups. Compared with the sham rats, the MI rats consistently developed severe cardiac function, myocardial fibrosis and infiltration of inflammatory cells including macrophages. Moreover, inflammatory pathway including activation of NLRP3 inflammasome, IL‐1β and autophagy was significantly up‐regulated in myocardial tissue, infiltrated cardiac macrophages and peritoneal macrophages of the MI rats. These impacts were reversed by Calhex231. In vitro, studies revealed that calindol and rapamycin exacerbated MI‐induced autophagy and NLRP3 inflammasome activation in peritoneal macrophages. Calhex231 and 3‐Methyladenine (a specific inhibitor of autophagy) attenuated both autophagy and NLRP3 inflammasome activation; however, the caspase‐1 inhibitor Z‐YVAD‐FMK did not. Our study indicated that Calhex231 improved cardiac function and ameliorated myocardial fibrosis post MI, likely via the inhibition of autophagy‐mediated NLRP3 inflammasome activation; this provides a new therapeutic target for ventricular remodelling‐related cardiovascular diseases.

AimsVascular smooth muscle cell (VSMC) proliferation plays a significant role in the development of various vascular disorders. However, the effect of cortistatin (CST) on VSMC proliferation remains unclear. Therefore, the purpose of our research aimed to study whether CST protected VSMCs from angiotensin II (Ang II)-induced proliferation and which mechanisms participated in the process.Main methodsCultured rat VSMCs were treated with Ang II with or without CST for 24 h. Cell proliferation rate was measured by cell counting kit-8 (CCK8) assay. The expressions of CST and its receptors were assessed by quantitative real-time PCR (qRT-PCR). The protein expression levels were analyzed by western blots. Immunofluorescence and transmission electron microscopy (TEM) were used to observe autophagy.Key findingsOur results showed that different concentrations of CST alleviated the Ang II-induced VSMC proliferation. The autophagy and reactive oxygen species (ROS) stimulated by Ang II were attenuated by CST. Furthermore, when the autophagy inhibitor 3-methyladenine (3-MA) was added, it exerted similar inhibition effects like CST, but didn't augment the protective role of CST on Ang II-induced VSMC autophagy and proliferation. Moreover, blocking somatostatin receptor 3 and 5 (SSTR3 and SSTR5) partially abrogated the suppressive effect of CST on Ang II-stimulated VSMC proliferation and autophagy.SignificanceThis study indicated that CST could ameliorate Ang II-stimulated VSMC proliferation by inhibiting autophagy partially through its receptors SSTR3 and SSTR5, providing a reasonable evidence for CST as a novel perspective therapeutic target of vascular diseases.

Background: The present study was designed to examine whether cortistatin (CORT) could protect rats from myocardial injury induced by subcutaneously injecting isoproterenol (ISO) and to clarify the possible mechanisms. Methods: Male Sprague-Dawley (SD) rats were placed at random into four groups: the control group, the ISO group, the ISO + CORT 25 mu g/(kg.d) group, and the ISO + CORT 50 mu g/(kg.d) group. Rat models of myocardial injury were established with the subcutaneous (s.c.) injections of 85 mg/kg ISO for 2 days. In the ISO + CORT 25 mu g/(kg.d) group and ISO + CORT 50 mu g/(kg.d) group, rats were given s.c. injections of CORT 25 mu g/(kg.d) and CORT 50 mu g/(kg.d) on the day before ISO, 3 days, respectively. Serum malondialdehyde (MDA) content, lactate dehydrogenase (LDH) activity, and creatine kinase isoenzyme (CK-MB) activity were measured by corresponding test kits. Western blot was applied to evaluate the expression of endoplasmic reticulum stress-related protein glucose regulatory protein 78 (GRP78), enhancer-binding protein homologous protein (CHOP), cysteinyl aspartate specific proteinase-12 (caspase-12), LC3-II, Beclin-1, and p62 in the rat myocardium. Results: CORT alleviated the increased enzyme activities of serum LDH and CK-MB, and content of MDA (a typical marker of lipid peroxidation) in rats induced by ISO. CORT also prevented pathological myocardial injury in rats induced by ISO. Moreover, CORT attenuated the increased protein levels of GRP78, CHOP, and caspase-12, and reduced the increase of LC3-II, LC3-II/I, Beclin-1, and p62 in rats induced by ISO. Conclusions: These data demonstrate that CORT can attenuate ISO-induced acute myocardial injury in rats likely by reducing lipid peroxidation, and inhibiting endoplasmic reticulum stress and autophagy. This supports CORT as a potentially being a new target for preventing and treating myocardial injury and its related disease.