G protein-regulated cell function is crucial for cardiomyocytes, and any deregulation of its gene expression or protein modification can lead to pathological cardiac hypertrophy. Herein, we report that protein prenylation, a lipidic modification of G proteins that facilitates their association with the cell membrane, might control the process of cardiomyocyte hypertrophy. We found that geranylgeranyl diphosphate synthase (GGPPS), a key enzyme involved in protein prenylation, played a critical role in postnatal heart growth by regulating cardiomyocyte size. Cardiac-specific knockout of GGPPS in mice led to spontaneous cardiac hypertrophy, beginning from week 4, accompanied by the persistent enlargement of cardiomyocytes. This hypertrophic effect occurred by altered prenylation of G proteins. Evaluation of the prenylation, membrane association and hydrophobicity showed that Rheb was hyperactivated and increased mTORC1 signalling pathway after GGPPS deletion. Protein farnesylation or mTORC1 inhibition blocked GGPPS knockdown-induced mTORC1 activation and suppressed the larger neonatal rat ventricle myocyte size and cardiomyocyte hypertrophy in vivo, demonstrating a central role of the FPP-Rheb-mTORC1 axis for GGPPS deficiency-induced cardiomyocyte hypertrophy. The sustained cardiomyocyte hypertrophy progressively provoked cardiac decompensation and dysfunction, ultimately causing heart failure and adult death. Importantly, GGPPS was down-regulated in the hypertrophic hearts of mice subjected to transverse aortic constriction (TAC) and in failing human hearts. Moreover, HPLC-MS/MS detection revealed that the myocardial farnesyl diphosphate (FPP):geranylgeranyl diphosphate (GGPP) ratio was enhanced after pressure overload. Our observations conclude that the alteration of protein prenylation promotes cardiomyocyte hypertrophic growth, which acts as a potential cause for pathogenesis of heart failure and may provide a new molecular target for hypertrophic heart disease clinical therapy.
Abstract Background Primary malignant tumors of the heart are rare. Although preoperative histological diagnosis is difficult, it has paramount value in therapeutic strategy development and prognostic estimation. Herein, we reported 2 cases of intracardiac tumors. Cases presentation Both patients presented to the hospital with heart-related symptoms. Echocardiography showed massive masses in the atrium and positron emission tomography–computed tomography (PET/CT) revealed hypermetabolism and invasiveness. One patient cannot take surgery due to extensive metastasis and poor condition. The other patient was primarily diagnosed with lymphoma, and surgery was not recommended. They successfully underwent intravenous atrial biopsy, and histological samples confirmed intimal sarcoma and diffuse large B cell lymphoma. Based on immunohistochemical and molecular assessments, targeted chemotherapy was administered, resulting in clinical and imaging remission at discharge. Conclusions Percutaneous intravenous catheter biopsy as a safe invasive test provides an accurate pathological diagnosis after imaging evaluation, and offers a therapeutic direction. Nonmalignant masses and some chemo-radiosensitive malignant tumors in the atrium could have good prognosis after targeted therapy.
Aims . To evaluate the effectiveness and safety of peritoneal dialysis (PD) in treating refractory congestive heart failure (RCHF) with cardiorenal syndrome (CRS). Methods . A total of 36 patients with RCHF were divided into type 2 CRS group (group A) and non-type 2 CRS group (group B) according to the patients’ clinical presentations and the ratio of serum urea to creatinine and urinary analyses in this prospective study. All patients were followed up till death or discontinuation of PD. Data were collected for analysis, including patient survival time on PD, technique failure, changes of heart function, and complications associated with PD treatment and hospitalization. Results . There were 27 deaths and 9 patients quitting PD program after a follow-up for 73 months with an average PD time of22.8±18.2months. A significant longer PD time was found in group B as compared with that in group A (29.0±19.4versus13.1±10.6months,p=0.003). Kaplan–Meier curves showed a higher survival probability in group B than that in group A (p<0.001). Multivariate regression demonstrated that type 2 CRS was an independent risk factor for short survival time on PD. The benefit of PD on the improvement of survival and LVEF was limited to group B patients, but absent from group A patients. The impairment of exercise tolerance indicated by NYHA classification was markedly improved by PD for both groups. The technique survival was high, and the hospital readmission was evidently decreased for both group A and group B patients. Conclusions . Our data suggest that PD is a safe and feasible palliative treatment for RCHF with type 2 CRS, though the long-term survival could not be expected for patients with the type 2 CRS. Registration ID Number is ChiCTR1800015910 .
Objective To investigate the effects of advanced glycation end products (AGEs) on activity and expression of endothelial nitric oxide synthase in cultured human umbilical vein endothelial cells (HUVECs). Methods AGE-modified bovein serum albumin (AGE-BSA) was prepared by incubated BSA with glucose at 37?℃ in vitro. HUVECs were co-incubated with different concentrations of AGE-BSA for 3, 6, 12, 24 and 48 hours respectively. The activity of eNOS is determined by the convertion of radiolabelled 3H-L-arginine to 3H-L-citrulline and eNOS expression levels were measured by Western blotting method. Results The activity of eNOS in HUVECs was partially activated under basic condition, and it was markedly increased by histamine (P0.001). AGE-BSA significantly inhibited the activity of eNOS in a concentration and time-dependent manner. The expression of eNOS had a significant reduction when HUVECs were incubated with AGE-BSA (200?mg·L -1) for 24 hours (P0.001)and a further decrease (P0.05, 48?h vs 24?h) for 48 hours. Conclusions AGE-BSA significntly inhibit the activity of eNOS,and this inhibited effect may be partially due to reduced eNOS expression.
Diabetic cardiomyopathy (DCM) is defined as ventricular dysfunction occurring independently of a recognized cause such as hypertension or coronary artery disease. Liver X receptor α (LXRα), a subtype of ligand-activated transcription factors LXRs, has been considered as a potential pharmacological target in the pathogenesis of cardiovascular and metabolic diseases. However, the potential mechanism of how LXRα is regulated in cardiomyocytes is still unclear. This study investigated the effect of activating LXRα with GW3965 on cardiomyocyte apoptosis and its upstream regulator in glucose-induced H9C2 cells. Our data indicated that GW3965 up-regulated the expression of LXRα, inhibited cardiomyocyte apoptosis, and altered the apoptosis-related proteins in glucose-induced H9C2 cells. In addition, GW3965 restored the mitochondrial membrane potential level and decreased the ROS production induced by glucose. Moreover, LXRα was confirmed as a direct target of microRNA-1 (miR-1) that was involved in cardiomyocyte apoptosis of DCM, and overexpression of miR-1 abrogated the inhibiting effect of GW3965 on glucose-induced apoptosis in H9C2 cells. This study highlights an important role of LXRα in the development of DCM and brings new insights into the complex mechanisms involved in the pathogenesis of DCM.
Abstract Several studies reported the role of endoplasmic reticulum stress (ERS) in vascular calcification. High‐mobility group box‐1 (HMGB‐1) plays a substantial role in diabetes and its complications. However, relatively little information is available regarding the association between HMGB‐1 and calcification, and the underlying mechanism has still remained elusive. Therefore, in the present study, we attempted to indicate whether HMGB‐1 could promote vascular calcification via ERS in diabetes. After induction of diabetes by Streptozotocin (STZ), mice were treated with glycyrrhizin (Gly) or 4‐phenylbutyrate (4‐PBA). Mineral deposition was confirmed by reverse transcription‐polymerase chain reaction (RT‐PCR) and calcium assay. In cell experiments, calcification of vascular smooth muscle cells (VSMCs) was performed with Alizarin Red staining, alkaline phosphatase (ALP) activity and RT‐PCR. Expression and location of HMGB‐1 in aortic tissue were detected by Western blotting, immunocytochemistry (ICC) and immunohistochemistry (IHC). Diabetic mice demonstrated increased HMGB‐1 expression, ERS and vascular calcification. However, inhibition of HMGB‐1 with Gly or inhibition of ERS with 4‐PBA ameliorated the enhanced vascular calcification and ERS in diabetic mice. In vitro experiments unveiled that inhibition of HMGB‐1 attenuated advanced glycation end products (AGEs)‐induced ERS in VSMCs. In addition, AGEs promoted translocation and secretion of HMGB‐1 in VSMCs, which was reversed by 4‐PBA. Moreover, VSMCs exhibited increased mineralization and osteogenic gene expressions in response to HMGB‐1 and AGEs. However, inhibition of ERS with 4‐PBA partially, although noticeably, attenuated VSMC calcification induced by HMGB‐1. Thus, diabetes induced translocation and secretion of HMGB‐1 via ERS, which resulted in calcification in diabetic mice and in AGEs‐treated VSMCs.
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