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.

Introduction:Hypertension poses a significant threat to human health through its induction of cardiac damage. The calcium-sensing receptor (CaSR) has been implicated in cardiovascular diseases; however, its specific role in cardiomyocyte injury in spontaneously hypertensive rats (SHRs) remains unclear. This study therefore investigated the effects of Calhex231, a CaSR antagonist, on cardiac damage in SHRs.Methods:Cardiac function and structure were evaluated by echocardiography, histological staining and transmission electron microscopy. To explore the underlying mechanisms, CaSR expression along with markers of mitophagy, autophagy and apoptosis were assessed in rat hearts tissues via Western blotting. Furthermore, mitochondrial membrane potential and intracellular calcium levels were measured in angiotensin II (Ang II)-treated cardiomyocytes at the cellular level.Results:Relative to WKY rats, SHRs showed elevated blood pressure, cardiac injury (hypertrophy, fibrosis, apoptosis), and upregulated CaSR, mitophagy and autophagy. Calhex231 reversed these in-vivo pathologies and, in vitro, protected cardiomyocytes against Ang II-induced apoptosis. This protection was achieved by inhibiting mitophagy/autophagy, lowering [Ca2+]i, and preserving mitochondrial membrane potential. The pivotal role of CaSR was underscored by the fact that its knockdown reproduced the protective effects against Ang II.Conclusion:These findings suggests that Calhex231 protects against cardiomyocyte apoptosis by inhibiting both the PINK1/Parkin-mediated mitophagy pathway and general autophagy. Therefore, targeting the CaSR represents a promising therapeutic strategy to prevent cardiac damage induced by 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.

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.

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BACKGROUND AND PURPOSE:Reducing hypertensive myocardial fibrosis is the fundamental approach to preventing hypertensive ventricular remodelling. C1q/TNF-related protein-3 (CTRP3) is closely associated with hypertension. However, the role and mechanism of CTRP3 in hypertensive myocardial fibrosis are unclear. In this study, we aimed to explore the effect of CTRP3 on hypertensive myocardial fibrosis and the potential mechanism. METHODS AND RESULTS:WKY and SHR rats were employed, blood pressure, body weight, heart weight, H/BW were measured, and fibrotic-related proteins, CTRP3 and Collagen I were tested in myocardium at 12 and 20 weeks by immunohistochemical staining and Western blotting, respectively. The results showed that compared with the WKY, SBP, DBP, mean arterial pressure and heart rate (HR) were all significantly increased in SHR at 12 and 20 weeks, while heart weight and H/BW were only increased at 20 weeks. Meanwhile, CTRP3 decreased, while Collagen I increased significantly in the SHR rat myocardium at 20 weeks, which compared to the WKY. Moreover, the expression of α-SMA increased from 12 weeks, Collagen I/III and MMP2/9 increased and TIMP-2 decreased until 20 weeks. In order to explore the function and mechanism of CTRP3 in hypertensive fibrosis, Angiotensin II (Ang II) was used to induce hypertension in primary neonatal rat cardiac fibroblasts in vitro . CTRP3 significantly inhibited the Ang II induced activation of fibrotic proteins, purinergic 2X7 receptor (P2X7R)-NLRP3 inflammasome pathway. The P2X7R agonist BzATP significantly exacerbated Ang II-induced NLRP3 inflammasome activation, which was decreased by the P2X7R antagonists A43079, CTRP3 and MCC950. CONCLUSION:CTRP3 expression was decreased in the myocardium of SHR rats, and exogenous CTRP3 inhibited Ang II-induced fibrosis in cardiac fibroblasts by regulating the P2X7R-NLRP3 inflammasome pathway, suggesting that CTRP3 is a potential drug for alleviating myocardial fibrosis in hypertensive conditions.

目的 探究组织因子途径抑制物（TFPI）对大鼠心肌缺血再灌注（I/R）及心肌细胞缺氧复氧（H/R）损伤的影响，并从心肌细胞凋亡的变化探索其机制。方法 在体内实验中，通过SD大鼠心脏原位结扎法可逆阻断前降支建立大鼠心肌I/R模型。将大鼠随机分为对照组、I/R组和I/R+rTFPI组，再灌注后3天采用HE染色观察大鼠心肌组织形态学变化，TTC染色法评估心肌梗死区范围，扫描透射电镜观察心肌超微结构损伤情况，Western-Blot法检测各组大鼠心肌组织中Bcl-2、Bax和cleaved-caspase-3蛋白的表达。在体外实验中，采用胰酶消化法及差速贴壁法培养SD乳鼠原代心肌细胞，用MIC101系统模拟心肌细胞I/R损伤，缺氧2小时、复氧12小时后建立体外心肌细胞缺氧/复氧（H/R）模型。将心肌细胞分为对照组、H/R组和H/R+rTFPI（10μg/L）组，用CCK8法检测心肌细胞活力，TUNEL法检测心肌细胞凋亡率，Western-blot方法检测心肌细胞中Bax、Bcl-2及cleaved-caspase-3蛋白的表达水平。结果 体内实验中，成功建立大鼠在体心肌I/R模型。HE染色结果显示I/R组较对照组心肌细胞坏死程度加重，I/R+rTFPI组较I/R组心肌细胞坏死程度减低；TTC染色示I/R+rTFPI组较I/R组心肌梗死范围减少了39.76%（P＜0.05）；扫描透射电镜观察显示I/R组凋亡及损伤程度较对照组加重，I/R+rTFPI组凋亡及损伤较I/R组减轻；Western-Blot结果示，再灌注3天后I/R组心肌组织Bcl-2的表达较对照组降低了53.43%（P＜0.05）、Bax和cleaved-caspase-3（P＜0.05）的表达较对照组分别增加了29.05%和73.25%（P＜0.05），而I/R+rTFPI组Bcl-2的表达水平较I/R组升高了55.01%（P＜0.05），Bax和cleaved-caspase-3的表达水平较I/R组分别降低了13.77%和24.25%（P＜0.05）。在体外实验中，CCK8检测结果显示H/R组细胞活力较对照组下降了29.70%（P＜0.05），H/R+rTFPI组细胞活力较H/R组升高了19.77%（P＜0.05）。TUNEL结果显示H/R组较对照组凋亡率增加了56.76%，H/R+rTFPI组细胞凋亡率较H/R组降低了24.55%（P＜0.05）。Western-blot结果示：H/R组细胞Bcl-2表达较对照组降低了46.92%，Bax表达较对照组增加了41.90%（P＜0.05），cleaved-caspase-3表达较对照组升高了2.68倍（P＜0.05）。H/R+rTFPI组Bcl-2表达较H/R组增加了28.24%（P＜0.05），Bax及cleaved-caspase-3表达较H/R组分别降低了26.34%和57.60%（P＜0.05）。结论 TFPI可显著拮抗心肌I/R和心肌细胞H/R损伤，此效应与其抑制心肌细胞凋亡有关。

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.

Mineralocorticoid receptor antagonists (MRA) have significant therapeutic effects on heart failure, hypertension, chronic kidney disease and primary aldosteronism. However, steroid MRA can cause hyperkalemia, deterioration of renal insufficiency, menstrual disorder and male breast development, and consequently has found limited clinical applications. In recent years, basic and clinical studies have confirmed that finerenone is a new non-steroidal MRA with high receptor affinity and selectivity, which can decrease adverse effects such as hyperkalemia and exert powerful cardioprotective effects. Herein, the structure, function, pharmacological mechanism and adverse effects of finerenone are summarized, and its cardiovascular protective effects and clinical applications are described in detail, to aid in understanding of the roles of finerenone in treating cardiovascular diseases and to explore future directions.

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.

Calcium-sensing receptor (CaSR), which was initially found in the parathyroid gland, is ubiquitously expressed and exerts specific functions in multiple cells, including immune cells. CaSR is functionally expressed on neutrophils, monocytes/macrophages, and T lymphocytes, but not B lymphocytes, and regulates cell functions, such as cytokine secretion, chemotaxis, phenotype switching, and ligand delivery. In these immune cells, CaSR is involved in the development of many diseases, such as sepsis, cryopyrin-associated periodic syndromes, rheumatism, myocardial infarction, diabetes, and peripheral artery disease. Since its discovery, it has been controversial whether CaSR is expressed and plays a role in immune cells. This article reviews current knowledge of the role of CaSR in immune cells.

Background: Essential hypertension (EH) patients, especially those along with hyperhomocysteinemia (HHcy), suffer from increased thrombotic events; however, the underlying mechanism remains unclear to date. Objective: We aimed to measure the plasma neutrophil extracellular trap (NET) levels and their role in the induction of procoagulant activity (PCA) in EH, as well as to evaluate the interactions with platelets or endothelial cells (ECs). Methods: The levels of NETs in the plasma of study subjects were detected by enzyme-linked immunosorbent assay. NET formation and the morphology of cells were analyzed using immunofluorescence or electron microscopy. PCA was analyzed by purified coagulation complex assays, clotting time, and fibrin turbidity. Phosphatidylserine (PS) exposure on ECs was detected with flow cytometry. Results: We observed that cell free-DNA and myeloperoxidase-DNA were significantly higher in EH patients compared to healthy controls. Moreover, NET formation was positively correlated with serum homocysteine (Hcy) levels in EH with HHcy. Furthermore, neutrophils from EH patients were more prone to produce NETs compared to those from controls. More importantly, immunofluorescence showed that HHcy could induce NET formation in vitro. Coagulation function assays showed that EH NETs significantly shortened coagulation time and increased thrombin and fibrin generation. The PCA was markedly attenuated approximately 70% by using DNase I. Additionally, isolated NETs from EH neutrophils induced platelet activation, exerted a strong cytotoxic effect on ECs, and converted them to a procoagulant phenotype. Conclusions: Our study revealed a previously unrecognized link between hypercoagulability and NETs in EH. Therefore, blocking NETs may represent a new therapeutic target for preventing thrombosis in these patients.

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.

Patients with essential hypertension (EH) and hyperhomocysteinemia (HHCY) suffer from more increased thrombotic events than those in EH alone. However, the underlying mechanisms for this effect are not well understood. This study hypothesized that neutrophil extracellular trap (NET) releasing may be triggered by HHCY in patients in EH, thereby predisposing them to a more hypercoagulable state. Using a modified-capture enzyme-linked immunosorbent assay (ELISA) method, we observed that cell-free DNA (CF-DNA) and myeloperoxidase DNA (MPO-DNA) in patients With EH and HHCY were significantly higher. The NET formation was also positively correlated with homocysteine levels, neutrophil-lymphocyte ratio (NLR), and hypercoagulable markers (thrombin-antithrombin complex, D-dimers). Furthermore, neutrophils from patients in EH with HHCY were found to be predisposed to amplified NET release when compared to patients in EH without HHCY or CTR. Coagulation function assays showed that NETs in patients With EH and HHCY resulted in a significantly increased ability to generate thrombin and fibrin than in those in EH without HHCY or CTR. These procoagulant effects of NETs in patients With EH and HHCY were markedly inhibited (approximately 70%) by the cleavage of NETs with DNase I. Isolated NETs from patients With EH and HHCY neutrophils also exerted a strong cytotoxic effect on endothelial cells (ECs), converted them to apoptosis. This study revealed a previously unrecognized association between the hypercoagulable state and neutrophils in patients With EH and HHCY. Therefore, blocking NETs may represent a new therapeutic objective for preventing thrombosis in these patients.

The exact mechanism of the prothrombotic state of essential hypertension (EH) patients remains elusive. Our objective was to assess whether phosphatidylserine (PS) exposure on endothelial cells (ECs), platelets, and microparticles (MPs) can account for the hypercoagulability in EH patients. PS exposure on cells and MPs, mainly from platelets and ECs was analyzed with flow cytometry. Procoagulant activity (PCA) was evaluated by purified coagulation complex assays, clotting time, and fibrin turbidity. We found that EH patients exhibited elevated levels of PS+ platelets, serum-cultured ECs, MPs, endothelial-derived MPs and platelet-derived MPs compared to the controls (all P < 0.05). Moreover, platelets and MPs from the patients and their sera-cultured ECs showed markedly enhanced intrinsic/extrinsic FXa, thrombin, and fibrin generation, and greatly shortened coagulation time. This PCA could be blocked approximately 80%, by the addition of lactadherin. Furthermore, we detected elevated levels of IL-8, IL-6, and TNF-α in EH patients could activate platelets/ECs and induce elevated PS exposure on their membranes. Our results suggest that inflammatory cytokines could enhance procoagulant activity of platelets and endothelial cells via their PS exposure in EH patients. As such, a PS blockade may be a viable therapeutic strategy for treating such patients.

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.

Increasing evidence suggests that the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome participates in cardiovascular diseases. However, its role and activation mechanism during hypertension remains unclear. In this study, we tested the role and mechanism of calcium-sensing receptor (CaSR) in NLRP3 inflammasome activation during hypertension. We observed that the expressions of CaSR and NLRP3 were increased in spontaneous hypertensive rats (SHRs) along with aortic fibrosis. In vascular smooth muscle cells (VSMCs), the activation of NLRP3 inflammasome associated with CaSR and collagen synthesis was induced by angiotensin II (Ang II). Furthermore, inhibition of CaSR and NLRP3 inflammasome attenuated proinflammatory cytokine release, suggesting that CaSR-mediated activation of the NLRP3 inflammasome may be a therapeutic target in aortic dysfunction and vascular inflammatory lesions.