RESUMO
INTRODUCTION: Percutaneous coronary intervention (PCI)-related myocardial infarction (type 4a MI) and major periprocedural myocardial injury have been demonstrated leading to poor prognosis of patients with coronary heart disease (CHD) undergoing elective PCI and still remain high occurrence even after the therapy of dual antiplatelet agents and statins. Proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab has been shown to be effectively in reducing the risk of acute MI (AMI). However, the effect of alirocumab on preventing PCI-related MI or major periprocedural myocardial injury in patients with CHD undergoing elective PCI remains uncertain. METHODS AND ANALYSIS: Alirocumab effect on Preventing Periprocedural ischaemic Events in coronary heart diseAse patients undergoing coronary StEnting trial is a multicentre, open-label, randomised controlled trial aiming to determine whether alirocumab could reduce the incidence of type 4a MI or major periprocedural myocardial injury in patients with CHD undergoing elective PCI. In total, 422 non-AMI CHD patients planned to undergo elective PCI will be randomly assigned to receive standard pharmacotherapy of CHD (control group) or additional use of subcutaneous alirocumab 75 mg 1 day before procedure (alirocumab group). The primary outcome is type 4a MI or major periprocedural myocardial injury defined as high-sensitivity cardiac troponin elevating above 5×99 th percentile upper reference limit in 48 hours after PCI. Patients will continue receiving standard pharmacotherapy or additional biweekly subcutaneous alirocumab 75 mg for 3 months according to the initial randomisation group. We will follow up for 3 months and record all the major adverse cardiovascular events (MACEs). Incidence of PCI-related MI or major periprocedural myocardial injury, and MACE in 3 months after PCI will be compared between control group and alirocumab group. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University with approval number: (2022)02-140-01. The results of this study will be reported through peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: ChiCTR2200063191.
Assuntos
Doença das Coronárias , Infarto do Miocárdio , Intervenção Coronária Percutânea , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Doença das Coronárias/complicações , Doença das Coronárias/cirurgia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como AssuntoRESUMO
Puerarin has multiple pharmacological effects and is widely prescribed for patients with cardiovascular diseases, including hypertension, cerebral ischemia, myocardial ischemia, diabetes mellitus, and arteriosclerosis. While puerarin is a useful therapeutic agent, its mechanisms of action have not been well defined. Understanding puerarin metabolism, in particular its interactions with metabolizing enzymes, will contribute to our understanding of its toxic and therapeutic effects and may help to elucidate potential negative drug-drug interactions. In this study, the major metabolite of puerarin was obtained from the urine of rats administered puerarin, by a semi-preparative high-performance liquid chromatography method. The major metabolite was identified as puerarin-7-O-glucuronide. In vitro, we used a UDP-glucuronosyltransferase (UGT) reaction screening method with 12 recombinant human UGTs to demonstrate that formation of puerarin-7-O-glucuronide was catalyzed by UGT1A1, 1A9, 1A10, 1A3, 1A6, 1A7, and 1A8. UGT1A1, 1A9, and 1A10 significantly catalyzed puerarin-7-O-glucuronide formation, and the activity of UGT1A1 was significantly higher than those of 1A9 and 1A10. The V (max) of UGT1A1 was two- to threefold higher than the levels of UGT1A9 or 1A10, with a lower K ( m ) value and a higher V (max)/K ( m ) value. The kinetics of puerarin-7-O-glucuronide formation catalyzed by UGT1A1 were similar to those of the pooled human liver microsomes (HLMs), with V (max) values of 186.3 and 149.2 pmol/min/mg protein, and K ( m ) values of 811.3 and 838.9 µM, respectively. Furthermore, bilirubin and ß-estradiol, probe substrates for UGT1A1, significantly inhibited the formation of puerarin-7-O-glucuronide in HLMs.
Assuntos
Glucuronosiltransferase/metabolismo , Isoflavonas/farmacocinética , Microssomos Hepáticos/enzimologia , Animais , Bilirrubina/metabolismo , Estradiol/metabolismo , Feminino , Glucuronídeos/metabolismo , Glucuronosiltransferase/genética , Humanos , Isoflavonas/metabolismo , Isoflavonas/urina , Cinética , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , UDP-Glucuronosiltransferase 1ARESUMO
Objective: The present observational study evaluated long-term management of hypertension in patients who received treatment with valsartan and amlodipine in a single-pill combination (Val/Aml SPC) in a real-world setting in China (Chinese Clinical Trial Registry number ChiCTR1900021324). Methods: This was a prospective, observational, multicenter, real-world registry study wherein patients with hypertension who had already received Val/Aml SPC (80/5 mg) for at least 4 weeks before study enrollment were observed for 1 year. Investigators recorded patient data every 3 months and essentially five times during the 1 year follow-up period. Effectiveness was assessed by the blood pressure (BP) control rate and average duration of treatment at the end of the study. Safety was monitored by the incidence of adverse events (AEs) and serious adverse events (SAEs). Results: Overall, 985 patients were enrolled (mean ± standard deviation [SD] age: 60.3 ± 11.5 years); of these, 894 were included in the full analysis set, 758 of whom completed the study. At baseline, BP was controlled (<140/90 mmHg) in 64.3% of patients on Val/Aml SPC for at least 4 weeks before enrollment. Office BP control rates significantly improved from baseline in 74.1% of patients at 1 year (p < .0001). Overall, 575 (87.0%) patients remained on Val/Aml SPC at 1 year (average exposure: 311.5 days). AEs were reported in 23.3% of patients. The majority of AEs were mild to moderate, and 0.6% of patients discontinued Val/Aml SPC because of SAEs. Conclusion: This study provides evidence that Val/Aml SPC effectively reduced BP over the long term among Chinese hypertensive patients, with a good adherence and tolerability profile, and that most hypertensive patients may benefit from this combination.
Assuntos
Anlodipino , Anti-Hipertensivos , Hipertensão/tratamento farmacológico , Valsartana , Idoso , Anlodipino/administração & dosagem , Anlodipino/efeitos adversos , Anlodipino/uso terapêutico , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/uso terapêutico , China , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Valsartana/administração & dosagem , Valsartana/efeitos adversos , Valsartana/uso terapêuticoRESUMO
This study aimed to investigate the anti-oxidant and anti-hypertrophic effects of puerarin-7-O-glucuronide, a water-soluble puerarin metabolite. The anti-oxidant effects of puerarin-7-O-glucuronide were assessed by measurement of intracellular superoxide levels, total superoxide dismutase (SOD) activity, total anti-oxidant capacity, and glutathione (GSH)/glutathione disulfide (GSSG) ratio in cultured neonatal rat cardiomyocytes (NRCMs) stimulated with the xanthine oxidase (XO)/xanthine (X) system or angiotensin II. The activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and expression of NADPH oxidase subunits p22phox and p47phox were determined. The anti-hypertrophic effects of puerarin-7-O-glucuronide in angiotensin II-challenged NRCMs were characterized by changes in cell morphology and expression of hypertrophic genes. In the pharmacokinetic study, the plasma concentration of puerarin-7-O-glucuronide was determined by rapid resolution-liquid chromatography-tandem mass spectrometry (RR-LC-MS/MS). Puerarin-7-O-glucuronide prevented XO/X-induced increase in intracellular superoxide production and decreases in total SOD activity, GSH/GSSG ratio, and total anti-oxidant capacity. Puerarin-7-O-glucuronide also reversed angiotensin II-induced increases in intracellular superoxide production and NADPH oxidase activity and decreases in total SOD activity. These anti-oxidant effects of puerarin-7-O-glucuronide were accompanied by downregulation of p22phox and p47phox. Furthermore, puerarin-7-O-glucuronide prevented angiotensin II-induced increases in cell surface area and perimeter, as well as changes in Nppa, Myh7, and Myh6. In the pharmacokinetic study, puerarin-7-O-glucuronide was cleared with a half-life of 0.94 h after intravenous administration. Puerarin could be detected in rat plasma, albeit in low concentration, as early as 5 min after intravenous administration of puerarin-7-O-glucuronide. These anti-oxidant and anti-hypertrophic properties of puerarin-7-O-glucuronide were similar to those of its parent compound puerarin. These results support the development of puerarin-7-O-glucuronide as a novel pharmaceutical agent for therapeutic application.
Assuntos
Angiotensina II/toxicidade , Antioxidantes/farmacologia , Cardiomegalia/prevenção & controle , Glucuronídeos/farmacologia , Isoflavonas/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Solventes/química , Água/química , Animais , Animais Recém-Nascidos , Antioxidantes/administração & dosagem , Antioxidantes/química , Antioxidantes/farmacocinética , Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Células Cultivadas , Feminino , Glucuronídeos/administração & dosagem , Glucuronídeos/química , Glucuronídeos/farmacocinética , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Injeções Intravenosas , Isoflavonas/administração & dosagem , Isoflavonas/química , Isoflavonas/farmacocinética , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Ratos Sprague-Dawley , Solubilidade , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Xantina/farmacologia , Xantina Oxidase/farmacologiaRESUMO
OBJECTIVE: To investegate the role of calcineurin (CaN) and its downstream nuclear factor of activated T-cells (NFATc3) in abdominal aorta restenosis following balloon dilatation in rats. METHODS: SD rats were randomly divided into sham-operated group, balloon group and cyclosporine A (CsA) group. The rats in the latter two groups were subjected to abdominal aorta injury with balloon dilatation, and those in CsA group were treated with CsA at the daily dose of 12.5 mg/kg from 3 days before the surgery to the end of the experiment. Thirty days afer the injury, histological analysis of the arterial wall was carried out with HE staining and immunohistochemistry. The expressions of CaN and NFATc3 in the abdominal aortas were detected with rea1-time PCR, and serum concentration of MCP-1 was determined using enzyme-linked immunosorbent assay. RESULTS: Intimal hyperplasia with irregular thickness of the neointima was observed in the aorta of rats with ballon injury. In rats with CsA treatment, the area of the intimal layers and the ratio of the intimal to the medial layers were obviously lower than those in the balloon injury group (P<0.05). Compared to those in the sham-operated group, the expressions of calcineurin protein and mRNA and NFATc3 mRNA in the arterial wall and serum level of MCP-1 increased significantly in the ballon injury group (P<0.05). CsA treatment significantly suppressed aorta restenosis and the alterations of CaN, NFATc3 and serum MCP-1 induced by ballon dilatation (P<0.05). CONCLUSIONS: CaN-NFATc3 signal transduction pathway mediates restenosis of rat abdominal aorta following ballon dilatation, and CsA can attenuate the restenosis by suppressing this pathway.
Assuntos
Aorta Abdominal/fisiopatologia , Calcineurina/metabolismo , Dilatação , Fatores de Transcrição NFATC/metabolismo , Transdução de Sinais , Animais , Cateterismo , Quimiocina CCL2/sangue , Constrição Patológica , Ensaio de Imunoadsorção Enzimática , Hiperplasia , Neointima/patologia , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Túnica Íntima/patologiaRESUMO
BACKGROUND: Non-O type of ABO blood group has been associated with a predisposition to coronary heart disease. It is thought that this association is partly mediated by increased cholesterol levels in non-O-type individuals. In this study, we sought to estimate the mediation effect size. METHODS AND RESULTS: In a group of individuals (n=6476) undergoing coronary angiography, we detected associations of non-O type with significant coronary artery disease with >50% stenosis in ≥1 coronary arteries (odds ratio, 1.24; 95% confidence interval, 1.10-1.39; P=2.6×10(-4)) and with prevalent or incident myocardial infarction (odds ratio, 1.22; 95% confidence interval, 1.09-1.37; P=1.2×10(-3)). Subjects of non-O type had higher levels of total cholesterol, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol (mean [SEM] in mmol/L: 4.931[0.021], 3.041 [0.018], and 3.805 [0.020] in non-O type compared with 4.778 [0.026], 2.906 [0.021], and 3.669 [0.024] in O type; P=3.8×10(-7), P=1.5×10(-7), and P=3.1×10(-7), respectively). Mediation analyses indicated that 10% of the effect of non-O type on coronary artery disease susceptibility was mediated by increased low-density lipoprotein cholesterol level (P=7.8×10(-4)) and that 11% of the effect of non-O type on myocardial infarction risk was mediated by raised low-density lipoprotein cholesterol level (P=2.0×10(-3)). CONCLUSIONS: In a model in which it is presumed that cholesterol is a mediator of the associations of ABO group with coronary artery disease and myocardial infarction, around 10% of the effect of non-O type on coronary artery disease and myocardial infarction susceptibility was mediated by its influence on low-density lipoprotein cholesterol level.
Assuntos
Sistema ABO de Grupos Sanguíneos/sangue , Colesterol/sangue , Doença das Coronárias/sangue , Idoso , LDL-Colesterol/sangue , Angiografia Coronária , Doença das Coronárias/epidemiologia , Doença das Coronárias/patologia , Estenose Coronária/etiologia , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Razão de Chances , Prevalência , Fatores de Risco , Triglicerídeos/sangueRESUMO
Cardiac hypertrophy is characterized by thickening myocardium and decreasing in heart chamber volume in response to mechanical or pathological stress, but the underlying molecular mechanisms remain to be defined. This study investigated altered miRNA expression and autophagic activity in pathogenesis of cardiac hypertrophy. A rat model of myocardial hypertrophy was used and confirmed by heart morphology, induction of cardiomyocyte autophagy, altered expression of autophagy-related ATG9A, LC3 II/I and p62 proteins, and decrease in miR-34a expression. The in vitro data showed that in hypertrophic cardiomyocytes induced by Ang II, miR-34a expression was downregulated, whereas ATG9A expression was up-regulated. Moreover, miR-34a was able to bind to ATG9A 3'-UTR, but not to the mutated 3'-UTR and inhibited ATG9A protein expression and autophagic activity. The latter was evaluated by autophagy-related LC3 II/I and p62 levels, TEM, and flow cytometry in rat cardiomyocytes. In addition, ATG9A expression induced either by treatment of rat cardiomyocytes with Ang II or ATG9A cDNA transfection upregulated autophagic activity and cardiomyocyte hypertrophy in both morphology and expression of hypertrophy-related genes (i.e., ANP and ß-MHC), whereas knockdown of ATG9A expression downregulated autophagic activity and cardiomyocyte hypertrophy. However, miR-34a antagonized Ang II-stimulated myocardial hypertrophy, whereas inhibition of miR-34a expression aggravated Ang II-stimulated myocardial hypertrophy (such as cardiomyocyte hypertrophy-related ANP and ß-MHC expression and cardiomyocyte morphology). This study indicates that miR-34a plays a role in regulation of Ang II-induced cardiomyocyte hypertrophy by inhibition of ATG9A expression and autophagic activity.
Assuntos
Angiotensina II/farmacologia , Autofagia/genética , Cardiomegalia/genética , Cardiomegalia/patologia , Proteínas de Membrana/genética , MicroRNAs/metabolismo , Miocárdio/patologia , Animais , Autofagia/efeitos dos fármacos , Sequência de Bases , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Proteínas de Membrana/metabolismo , MicroRNAs/genética , Dados de Sequência Molecular , Miocárdio/ultraestrutura , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , RNA Interferente Pequeno/metabolismo , Ratos Sprague-Dawley , Sístole/efeitos dos fármacos , Vacúolos/efeitos dos fármacos , Vacúolos/ultraestruturaRESUMO
Dysregulated autophagy may lead to the development of disease. Role of autophagy and the diagnostic potential of microRNAs that regulate the autophagy in cardiac hypertrophy have not been evaluated. A rat model of cardiac hypertrophy was established using transverse abdominal aortic constriction (operation group). Cardiomyocyte autophagy was enhanced in rats from the operation group, compared with those in the sham operation group. Moreover, the operation group showed up-regulation of beclin-1 (an autophagy-related gene), and down-regulation of miR-30 in cardiac tissue. The effects of inhibition and over-expression of the beclin-1 gene on the expression of hypertrophy-related genes and on autophagy were assessed. Angiotensin II-induced myocardial hypertrophy was found to be mediated by over-expression of the beclin-1 gene. A dual luciferase reporter assay confirmed that beclin-1 was a target gene of miR-30a. miR-30a induced alterations in beclin-1 gene expression and autophagy in cardiomyocytes. Treatment of cardiomyocytes with miR-30a mimic attenuated the Angiotensin II-induced up-regulation of hypertrophy-related genes and decreased in the cardiomyocyte surface area. Conversely, treatment with miR-30a inhibitor enhanced the up-regulation of hypertrophy-related genes and increased the surface area of cardiomyocytes induced by Angiotensin II. In addition, circulating miR-30 was elevated in patients with left ventricular hypertrophy, and circulating miR-30 was positively associated with left ventricular wall thickness. Collectively, these above-mentioned results suggest that Angiotensin II induces down-regulation of miR-30 in cardiomyocytes, which in turn promotes myocardial hypertrophy through excessive autophagy. Circulating miR-30 may be an important marker for the diagnosis of left ventricular hypertrophy.
Assuntos
Angiotensina II , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Hipertrofia/metabolismo , MicroRNAs/genética , Angiotensina II/genética , Angiotensina II/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/genética , Proteína Beclina-1 , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/fisiopatologia , Humanos , Hipertrofia/diagnóstico , Hipertrofia/genética , Hipertrofia/fisiopatologia , MicroRNAs/sangue , MicroRNAs/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Ratos , Regulação para CimaRESUMO
Puerarin has multiple pharmacological effects and is widely prescribed for patients with cardiovascular diseases including hypertension, cerebral ischemia, myocardial ischemia, diabetes mellitus, and arteriosclerosis. We have successfully prepared puerarin-loaded solid lipid nanoparticles (Pue-SLNs) for oral administration. Pue-SLNs are prepared using monostearin, soya lecithin, and poloxamer 188. SLNs may alter the course of puerarin absorption predominantly to and through lymphatic routes and regions, presumably following a transcellular path of lipid absorption, especially by enterocytes and polar epithelial cells of the intestine. The alteration of absorption might influence the metabolic profile of puerarin when incorporated into SLNs. In the present study, we investigated the metabolic profile of puerarin in rat plasma and urine using rapid resolution liquid chromatography-tandem mass spectrometry after a single-dose intragastric administration of Pue-SLNs in comparison with puerarin suspension. Two glucuronidated metabolites of puerarin, puerarin-4'-O-glucuronide and puerarin-7-O-glucuronide, were detected in rat plasma and urine after intragastric administration of Pue-SLNs, with the latter acting as the major metabolite. Similar results were found in rat plasma and urine after intragastric administration of puerarin suspension. The results suggest that incorporation of puerarin into SLNs does not change either the position of glucuronidation or the metabolic pathway of puerarin in rats.
Assuntos
Isoflavonas/metabolismo , Lipídeos/administração & dosagem , Nanopartículas/administração & dosagem , Absorção , Animais , Feminino , Glucuronídeos/sangue , Glucuronídeos/metabolismo , Glucuronídeos/urina , Isoflavonas/administração & dosagem , Isoflavonas/sangue , Isoflavonas/urina , Lipídeos/química , Masculino , Metaboloma , Nanopartículas/química , Ratos , Ratos Sprague-DawleyRESUMO
The pathogenesis of coronary artery disease (CAD) is closely associated with inflammation, in which human leukocyte antigens (HLA), especially HLA-DR molecules, play important roles. However, whether various HLA-DRB1 alleles can contribute differing susceptibility to CAD has not been elucidated. In this study, we demonstrated a significantly lower frequency of HLA-DRB1*12:02:01 in the CAD group (9.82%) than in controls (18.22%) after age adjustment (odds ratio [OR] = 0.489, p = 0.0036). Logistic regression analysis indicated that carriers of HLA-DRB1*12:02:01 exhibited a lower risk of CAD events after adjustment for age, gender, and other confounders (p = 0.014, OR = 0.526 [95% confidence interval 0.314-0.878]). The female carriers of HLA-DRB1*12:02:01 exhibited a much lower risk of CAD events both before (OR = 0.424, p = 0.0387) and after age adjustment (OR = 0.302, p = 0.0058). In another female cohort, the frequency of HLA-DRB1*12:02:01 also differed between the female CAD group (8.23%) and the female controls (18.75%; OR = 0.389, p = 0.0116). Further analysis indicated that HLA-DRB1*12:02:01 was not frequent in participants with premature CAD or more diseased blood vessels. In summary, our data demonstrate that HLA-DRB1*12:02:01 plays a protective role against CAD in southern Han Chinese, especially in females. The mechanism behind the protective effect requires further exploration.