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1.
J Interv Cardiol ; 2021: 6659261, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33976590

RESUMO

MitraClip edge-to-edge (E2E) repair system is the only transcatheter device recommended in the current guidelines for treating mitral regurgitation (MR). The percutaneous femoral venous transseptal access of MitraClip requires a complex steerable delivery system and may thus be technically complex to optimally position and deploy the clip onto the mitral valve. A transapical approach for E2E repair has been devised to treat MR for the ease of operation (ValveClamp system, Hanyu Medical Technology, Shanghai). The first-in-human study of ValveClamp has demonstrated its early feasibility and effectiveness for the treatment of patients with degenerative MR. Transesophageal echocardiography (TEE) is the only imaging modality required for intraoperative guidance of ValveClamp implantation. Successful implantation depends on accurate localization and orientation of the clamp and efficient intraoperative communication between the echocardiographer and the intervention team. Thus, the focus of this review is on elaborating how two-dimensional (2D) and three-dimensional (3D) TEE are used in clinical practice to guide ValveClamp implantation and it may facilitate the understanding of simplicity and safety of this novel procedure. We also describe the implementation of several novel advancements in 3D TEE imaging, which improve the confidence of image interpretation for intraoperative guidance and expedite implantation times.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33951285

RESUMO

OBJECTIVES: This multicenter, prospective clinical study investigates whether the microelectromechanical-systems-(MEMS)-sensor pressure microcatheter (MEMS-PMC) is comparable to a conventional pressure wire in fractional flow reserve (FFR) measurement. BACKGROUND: As a conventional tool for FFR measurement, pressure wires (PWs) still have some limitations such as suboptimal handling characteristics and unable to maintain the wire position during pullback assessment. Recently, a MEMS-PMC compatible with any 0.014″ guidewire is developed. Compared with the existing optical-sensor PMC, this MEMS-PMC has smaller profiles at both the lesion crossing and sensor packaging areas. METHODS: Two hundred and forty-two patients with visually 30-70% coronary stenosis were enrolled at four centers. FFR was measured first with the MEMS-PMC, and then with the PW. The primary endpoint was the Bland-Altman mean bias between the MEMS-PMC and PW FFR. RESULTS: From the 224-patient per-protocol data, quantitative coronary angiography showed 17.9% and 55.9% vessels had diameter < 2.5 mm and stenosis >50%, respectively. The two systems' mean bias was -0.01 with [-0.08, 0.06] 95% limits-of-agreement. Using PW FFR≤0.80 as cutoff, the MEMS-PMC per-vessel diagnostic accuracy was 93.4% [95% confidence interval: 89.4-96.3%]. The MEMS-PMC's success rate was similar to that of PW (97.5 vs. 96.3%, p = .43) with no serious adverse event, and its clinically-significant (>0.03) drift rate was 43% less (9.5 vs. 16.7%, p = .014). CONCLUSIONS: Our study showed the MEMS-PMC is safe to use and has a minimal bias equal to the resolution of current FFR systems. Given the MEMS-PMC's high measurement accuracy and rapid-exchange nature, it may become an attractive new tool facilitating routine coronary physiology assessment.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33964182

RESUMO

OBJECTIVES: The aim of this study was to investigate the influences of accumulated experience on rotational atherectomy (RA) operation regarding to in-hospital outcomes in the drug-eluting stent (DES) era. METHODS: Between 2015 and 2019, 540 de novo lesions with calcified coronary lesions treated by RA and DES implantation at our center were retrospectively assessed. In-hospital major adverse cardiac events (MACE) were defined as all cause death, cardiac death, target vessel revascularization, and stroke. RESULTS: From 2015 to 2019, RA operations were 22, 60, 102, 157, and 199 cases, respectively. Rates of procedural complications were 4.5, 3.3, 11.8, 8.3, and 7.5%, respectively. Rates of in-hospital MACE were 0, 0, 3.9, 2.5, and 2.0%, respectively. Compared with planned RA, bailout RA was associated with more contrast use (207.5 ± 82.8 ml vs. 189.2 ± 70.0 ml, p = .008). As for procedural complications and in-hospital outcomes, no differences were observed between two strategies. Logistic regression revealed that hypertension was independently associated with complications (OR 5.830, 95% CI 1.382-24.591, p = .016). For MACE, independent risk factors were heart failure (OR 17.593, 95% CI 1.475-209.816, p = .023) and procedural complications (OR 127.629, 95% CI 15.135-1,076.258, p < .001). CONCLUSIONS: Along with the rapid increase of RA use and accumulated experience, rates of complications and MACE went up first and then dropped down. Hypertension was found to be an independent risk factor of procedural complications. For in-hospital MACE, independent risk factors were heart failure and procedural complications.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33958549

RESUMO

ABSTRACT: Warfarin is a commonly prescribed anticoagulant for valvular heart disease that plays an important role in clinical management to prevent thrombotic events. In this study, we aim to perform a comprehensive study to investigate the genetic biomarkers of stable warfarin dose in the Han Chinese population. We performed an integrative study on 211 Han Chinese patients with valvular heart disease. A total of 40 single nucleotide polymorphisms (SNPs) in 10 important genes (CYP2C9, VKORC1, ABCB1, CYP4F2, APOE, PROC, GGCX, EPHX1, CALU and SETD1A) which are involved in the warfarin metabolic pathway and equilibrium of coagulation and anti-coagulation were selected. We applied MassARRAY technology to genotype the 40 SNPs identified in these Han Chinese patients. Our results showed that 13 SNPs on 6 genes (CYP2C9, VKORC1, ABCB1, PROC, EPHX1 and SETD1A) were associated with the individual stable warfarin dose. Two VKORC1 SNPs (rs9934438 and rs2359612) were the strongest genetic factors determining warfarin dose requirements (P=8×10-6 and 9×10-6, respectively). Rs4889599 in SETD1A was first reported to be associated with warfarin dose at a significant level of 0.001 in our study (Padjust=0.040 after Bonferroni correction). We discovered that, genetic variants in CYP2C9, VKORC1, ABCB1, PROC, EPHX1 and SETD1A may affect the stable warfarin dose requirement in Han Chinese patients with valvular disease. The discovery of these potential genetic markers will facilitate the development of advanced personalized anticoagulation therapy in Han Chinese patients.

5.
BMC Cardiovasc Disord ; 21(1): 232, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962571

RESUMO

BACKGROUND: The jailed balloon technique is widely used for coronary bifurcation lesions, but a residual risk of SB occlusion remains, necessitating SB rewiring and further interventions, including balloon inflation or stenting, which may result in failure and SB loss. This study introduced a novel modified technique of small side branch (SB) protection, namely, double kissing inflation outside the stent (DKo) technique, for coronary bifurcations without the need for SB rewiring. METHODS: We performed the DKo technique in consecutive patients in our center from 1/2019 to 12/2019. The procedure was as follows. We inserted a guide wire into both branches followed by proper preparation. The SB balloon was simultaneously inflated with main vessel (MV) stenting. The SB balloon remained in situ until it was kissing inflated with postdilation of the bifurcation core, which is different from traditional strategies. The proximal optimization technique was performed with a short noncompliant balloon strictly not exceeding the bifurcation. Rates of SB loss and in-hospital outcomes were evaluated. RESULTS: The technique was successfully performed in all 117 enrolled patients without any rewiring or SB loss. The mean lesion lengths of the MV and SB were 38.3 ± 19.9 mm and 11.7 ± 7.1 mm, respectively. On average, 1.5 ± 0.6 stents were used per patient, while the mean pressure of the SB balloon was 7.4 ± 3.1 atm. DKo achieved excellent procedural success in the proximal and distal MVs: increased minimal lumen diameter (0.64 ± 0.58 mm to 3.05 ± 0.38 mm, p < 0.001; 0.57 ± 0.63 mm to 2.67 ± 0.35 mm, p < 0.001) and low residual stenosis (11.4 ± 3.4%; 7.2 ± 4.6%). DKo secured the patency of the SB without any rewiring and improved the SB stenosis with minimal lumen diameter (0.59 ± 0.48 mm to 1.20 ± 0.42 mm, p < 0.001) and stenosis (71.9 ± 19.4% to 42.2 ± 14.0%, p < 0.001). No MACE was noted in the hospital. CONCLUSIONS: DKo for bifurcation lesions was shown to be acceptable with high procedural success and excellent SB protection.

6.
Cell Prolif ; : e13051, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33973685

RESUMO

BACKGROUND: Ischaemic preconditioning elicited by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischaemic insult. Here, we test the hypothesis that short-term non-ischaemic stimulation of hypertrophy renders the heart resistant to subsequent ischaemic injury. METHODS AND RESULTS: Transient transverse aortic constriction (TAC) was performed for 3 days in mice and then withdrawn for 4 days by aortic debanding, followed by subsequent exposure to myocardial ischaemia-reperfusion (I/R) injury. Following I/R injury, myocardial infarct size and apoptosis were significantly decreased, and cardiac dysfunction was markedly improved in the TAC preconditioning group compared with the control group. Mechanistically, TAC preconditioning markedly suppressed I/R-induced autophagy and preserved autophagic flux by deacetylating SOD2 via a SIRT3-dependent mechanism. Moreover, treatment with an adenovirus encoding SIRT3 partially mimicked the effects of hypertrophic preconditioning, whereas genetic ablation of SIRT3 in mice blocked the cardioprotective effects of hypertrophic preconditioning. Furthermore, in vivo lentiviral-mediated knockdown of Beclin 1 in the myocardium ameliorated the I/R-induced impairment of autophagic flux and was associated with a reduction in cell death, whereas treatment with a lentivirus encoding Beclin 1 abolished the cardioprotective effect of TAC preconditioning. CONCLUSIONS: The present study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Specifically, TAC preconditioning reduced myocardial autophagic cell death in a SIRT3/SOD2 pathway-dependent manner.

7.
J Interv Cardiol ; 2021: 8835104, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33935602

RESUMO

Objective: The initial recanalization rate of coronary chronic total occlusions (CTOs) is >85% when performed by experienced operators, but only 10% of prior failed CTO patients receive reattempted recanalization. This retrospective study analyzed the success rate and strategies used in reattempt percutaneous coronary intervention (PCI) of CTOs after prior failures. Methods: Overall, 206 patients with 212 CTOs were enrolled. All patients with prior recanalization failures received reattempt PCIs from January 2015 to March 2019 at Zhongshan Hospital, Fudan University. Data on clinical factors (age, sex, comorbidities, left ventricular ejection fraction, history of cigarette usage, and revascularization), angiographic characteristics of CTOs (target lesion, Japanese Chronic Total Occlusion (J-CTO) score, the morphology of CTO lesions, and collateral channel scale), strategies (procedural approach and use of devices), and major adverse events were obtained and analyzed. Results: The mean age of enrolled patients was 60.96 ± 12.36 years, with a male predominance of 90.3%. Of the patients, 47.1% had a prior myocardial infarction and 70.4% underwent stent implantation previously, while the in-stent occlusion rate was 6.6%. CTOs were primarily localized in the left anterior descending artery (43.9%) and the right coronary artery (43.9%). 80.7% of lesions were classified as very difficult (J-CTO score ≥3), and the overall success rate was 81.1%. In multivariable regression analysis, J-CTO score, collateral channel scale, application of coronary multispiral computed tomography angiography, dual injection, intravascular ultrasound, active greeting technique, parallel wiring, and CTO morphology were predictors of recanalization success. There were no significant differences in rates of procedural complications between the final recanalization success and failure groups. Conclusions: Recanalization of complex CTOs is associated with high success rate and low complication rates when performed by high-volume CTO operators and after multiple reattempts.

8.
BMC Cardiovasc Disord ; 21(1): 218, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931019

RESUMO

BACKGROUND: Due to the technical limitations of coronary artery angiography (CAG), ramus intermedius (RI) is sometimes difficult to distinguish from a high-origin obtuse marginal branch or a high-origin diagonal branch. This study sought to investigate the role of intravascular ultrasonography (IVUS) in the rectification of angiographically judged RI. METHODS: This study retrospectively analyzed 165 patients who were reported to have an RI based on CAG and underwent IVUS implementation from 02/01/2009 to 31/12/2019 in Zhongshan Hospital, Fudan University. Taking IVUS as the gold standard, we calculated the accuracy of RI identification by CAG and evaluated the impact of RI on revascularization strategy. RESULTS: Among the 165 patients, 89 patients (54%) were demonstrated to have an RI on IVUS (IVUS-RI), 32 patients (19%) were identified to have a high-origin diagonal branch on IVUS (IVUS-h-D), and 44 patients (27%) had an actual high-origin obtuse marginal artery on IVUS (IVUS-h-OM). Among 84 patients who underwent one-stent crossover stenting because of left main furcation lesions (48 patients in the IVUS-RI group, 12 patients in the IVUS-h-D group, and 24 in the IVUS-h-OM group), 14.6% of patients in the IVUS-RI group, 33.3% in the IVUS-h-D group and 0% in the IVUS-h-OM group had CAG-RI compromise (P = 0.02), which was defined as severe stenosis of the RI ostium (> 75%) or significant RI flow impairment (TIMI < 3). CONCLUSIONS: Only 54% of CAG-RIs were confirmed by IVUS, which indicates the necessity of preintervention IVUS to distinguish real RIs from other branches in LM furcation lesions.

9.
Circ Heart Fail ; 14(4): e007901, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33866828

RESUMO

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial. METHODS: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region. RESULTS: Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction P>0.05). CONCLUSIONS: Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

12.
Redox Biol ; 43: 101960, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33910156

RESUMO

Brief episodes of ischaemia and reperfusion render the heart resistant to subsequent prolonged ischaemic insult, termed ischaemic preconditioning. Here, we hypothesized that transient non-ischaemic stress by hypertrophic stimulation would induce endogenous cardioprotective signalling and enhance cardiac resistance to subsequent ischaemic damage. Transient transverse aortic constriction (TAC) or Ang-Ⅱ treatment was performed for 3-7 days in male mice and then withdrawn for several days by either aortic debanding or discontinuing Ang-Ⅱ treatment, followed by subsequent exposure to regional myocardial ischaemia by in situ coronary artery ligation. Following ischaemia/reperfusion (I/R) injury, myocardial infarct size and apoptosis were markedly reduced and contractile function was significantly improved in the TAC preconditioning group compared with that in the control group. Similar results were observed in mice receiving Ang-Ⅱ infusion. Mechanistically, TAC preconditioning enhanced ALDH2 activity, promoted AMPK activation and improved mitochondrial energy metabolism by increasing myocardial OXPHOS complex expression, elevating the mitochondrial ATP content and improving viable myocardium glucose uptake. Moreover, TAC preconditioning significantly mitigated I/R-induced myocardial iNOS/gp91phox activation, inhibited endoplasmic reticulum stress and ameliorated mitochondrial impairment. Using a pharmacological approach to inhibit AMPK signalling in the presence or absence of preconditioning, we demonstrated AMPK-dependent protective mechanisms of TAC preconditioning against I/R injury. Furthermore, treatment with adenovirus-encoded ALDH2 partially emulated the actions of hypertrophic preconditioning, as evidenced by improved mitochondrial metabolism, inhibited oxidative stress-induced mitochondrial damage and attenuated cell death through an AMPK-dependent mechanism, whereas genetic ablation of ALDH2 abrogated the aforementioned actions of TAC preconditioning. The present study demonstrates that preconditioning with hypertrophic stress protects the heart from I/R injury via mechanisms that improve mitochondrial metabolism, reduce oxidative/nitrative stress and inhibit apoptosis. ALDH2 is obligatorily required for the development of cardiac hypertrophic preconditioning and acts as the mediator of this process.

13.
J Atheroscler Thromb ; 2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33867420

RESUMO

AIMS: In this study, we integrated two randomized control trials, PROSPECTIVE and IMPACT, to address the effect of probucol on cerebrocardiovascular events and carotid intima-media thickness (IMT) in Japanese, Korean, and Chinese patients with coronary artery disease (CAD). METHODS: A total of 1,025 patients from the PROSPECTIVE and IMPACT studies were enrolled. The time to the first major adverse cerebrocardiovascular event, in addition to carotid IMT and lipid levels, was compared between the control and probucol groups. RESULTS: In the integrated analysis, the adjusted hazard ratio (HR) and 95% confidence interval (CI) were 0.67 and 0.44-1.03, respectively, indicating a tendency to show the effect of probucol on cerebrocardiovascular events in secondary prevention. We also found no significant differences between the control and probucol groups in the mean IMT of the carotid arteries and its changes. However, we found a significant decrease in cerebrocardiovascular events in patients with reduced levels of HDL cholesterol (HDL-C) (≥ 6.25 mg/dL) compared with those with levels <6.25 mg/dL (p=0.024), without any increase in adverse events such as severe ventricular arrhythmias. CONCLUSION: We demonstrated a marginal effect of probucol on cerebrocardiovascular events in Asian patients with CAD, with reasonable safety profiles. A larger study may be needed to support the effect of probucol for cardiovascular prevention.

15.
Endocr Rev ; 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33693711

RESUMO

The endoplasmic reticulum (ER) hosts linear polypeptides and fosters natural folding of proteins through ER-residing chaperones and enzymes. Failure of the ER to align and compose proper protein architecture leads to accumulation of misfolded/unfolded proteins in the ER lumen, which disturbs ER homeostasis to provoke ER stress. Presence of ER stress initiates the cytoprotective unfolded protein response (UPR) to restore ER homeostasis or instigates a rather maladaptive UPR to promote cell death. Although a wide array of cellular processes such as persistent autophagy, dysregulated mitophagy, and secretion of pro-inflammatory cytokines may contribute to the onset and progression of cardiometabolic diseases, it is well perceived that ER stress also evokes onset and development of cardiometabolic diseases, particularly, cardiovascular diseases, diabetes mellitus, obesity, and chronic kidney disease. Meanwhile, these pathological conditions further aggravate ER stress, creating a rather vicious cycle. Here in this review, we aimed at summarizing and updating the available information on ER stress in cardiovascular diseases, diabetes mellitus, obesity, and chronic kidney disease, hoping to offer novel insights for the management of these cardiometabolic comorbidities through regulation of ER stress.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33709255

RESUMO

Data on ischemic and bleeding outcomes after percutaneous coronary intervention (PCI) in high bleeding risk (HBR) patients with chronic kidney disease (CKD) are scarce. We aimed to evaluate the association between CKD and ischemic and bleeding outcomes in HBR patients who underwent PCI. Among 10,502 patients in the four post-approval registries evaluating patients undergoing PCI, 2,300 patients presented with at least one major or two minor ARC-HBR criteria. CKD was defined as eGFR < 60 mL/min/1.73 m2. These HBR patients were divided into 3 groups: eGFR < 30 mL/min/1.73 m2 defined as severe CKD (N = 221), eGFR 30- < 60 mL/min/1.73 m2 defined as moderate CKD (N = 970), eGFR ≥ 60 mL/min/1.73 m2 defined as no CKD (N = 1,109). The primary endpoint was the composite of cardiac death, myocardial infarction, or stent thrombosis, and the safety endpoint was major bleeding up to 4-year follow-up. HBR patients with CKD were more often female and had higher rates of comorbidities compared to those without CKD. Reduced renal function was associated with higher rates of the primary endpoint (severe CKD vs. moderate CKD vs. no CKD: 30.2% vs. 12.5% vs. 9.1%, P < 0.01) as well as major bleeding (10.3% vs. 8.9% vs. 6.4%, P = 0.03). After adjustment, severe CKD and moderate CKD in HBR patients remained independent predictors for the primary endpoint (HR [95%CI] 2.84 [1.94-4.16], P < 0.01, 1.48 [1.10-2.00], P < 0.01) compared to those with no CKD. However, decreased renal function was no longer significantly associated with major bleeding after adjustment. In conclusions, in HBR patients undergoing PCI, CKD has an important impact on major ischemic events after PCI.

17.
J Am Heart Assoc ; 10(7): e015292, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33728933

RESUMO

Background Small intestinal bacterial overgrowth (SIBO) is a common pathological condition of intestinal microbiota. The prevalence of SIBO and its prognostic value in patients with heart failure (HF) are unknown. Methods and Results A total of 287 patients tested for SIBO using lactulose hydrogen-methane breath test were evaluated. At least 1 of the following criteria fulfilled was SIBO positive: patients with fasting hydrogen level ≥20 parts per million (ppm) or a ≥20 ppm rise in hydrogen by 90 minutes were diagnosed with SIBO (H2) positive; and patients with methane levels ≥10 ppm at any test point were diagnosed with SIBO (CH4) positive. The association between SIBO and the composite of cardiovascular death and HF rehospitalization was investigated. In 287 consecutive patients with HF, 128 (45%) were positive for SIBO. Our result showed SIBO increased the risk of HF rehospitalization in patients with HF with reduced ejection fraction (P<0.001), and the risk of cardiovascular death in patients with HF with preserved EF (P=0.011). SIBO was an independent risk factor of primary end point in patients with HF (hazard ratio [HR], 2.13; 95% CI; 1.26-3.58; P=0.005). In addition, SIBO (CH4) showed a prognostic value on adverse outcomes (HR, 2.35; 95% CI, 1.38-4.02; P<0.001), whereas the association between SIBO (H2) and outcomes was not statistically significant. Conclusions There was high prevalence of SIBO in patients with HF, and SIBO was independently associated with poor outcomes. Proactive treatment for SIBO may provide extra benefit for patients with HF.

18.
Life Sci ; 273: 119239, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33652033

RESUMO

Our previous work revealed the protective effect of Qiliqiangxin (QLQX) on cardiac microvascular endothelial cells (CMECs), but the underlying mechanisms remain unclear. We aimed to investigate whether QLQX exerts its protective effect against high-concentration angiotensin II (Ang II)-induced CMEC apoptosis through the autophagy machinery. CMECs were cultured in high-concentration Ang II (1 µM) medium in the presence or absence of QLQX for 48 h. We found that QLQX obviously inhibited Ang II-triggered autophagosome synthesis and apoptosis in cultured CMECs. QLQX-mediated protection against Ang II-induced CMEC apoptosis was reversed by the autophagy activator rapamycin. Specifically, deletion of ATG7 in cultured CMECs indicated a detrimental role of autophagy in Ang II-induced CMEC apoptosis. QLQX reversed Ang II-mediated ErbB2 phosphorylation impairment. Furthermore, inhibition of ErbB2 phosphorylation with lapatinib in CMECs revealed that QLQX-induced downregulation of Ang II-activated autophagy and apoptosis was ErbB2 phosphorylation-dependent via the AKT-FoxO3a axis. Activation of ErbB2 phosphorylation by Neuregulin-1ß achieved a similar CMEC-protective effect as QLQX in high-concentration Ang II medium, and this effect was also abolished by autophagy activation. These results show that the CMEC-protective effect of QLQX under high-concentration Ang II conditions could be partly attributable to QLQX-mediated ErbB2 phosphorylation-dependent downregulation of autophagy via the AKT-FoxO3a axis.


Assuntos
Angiotensina II/toxicidade , Autofagia , Medicamentos de Ervas Chinesas/farmacologia , Células Endoteliais/efeitos dos fármacos , Proteína Forkhead Box O3/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Animais , Apoptose , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Proteína Forkhead Box O3/genética , Masculino , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Ratos Sprague-Dawley , Receptor ErbB-2/genética , Transdução de Sinais , Vasoconstritores/toxicidade
20.
Theranostics ; 11(8): 3916-3931, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33664870

RESUMO

Therapeutic angiogenesis is one promising strategy for the treatment of ischemic heart disease, which is the leading cause of death globally. In recent years, extracellular vesicles (EVs) have quickly gained much attention as a cell-free approach to stimulate angiogenesis. However, clinical applications of EVs are limited by their insufficient targeting capability. Herein, we introduce a method to enhance therapeutic angiogenesis based on platelet membrane-engineered EVs. METHODS: Platelet-mimetic EVs (P-EVs) were fabricated by fusing the membranes of EVs with platelet membranes by extrusion. A mouse model of myocardial ischemia reperfusion (MI/R) was established and injected with PBS, EVs, and P-EVs to evaluate their targeting ability and therapeutic angiogenesis efficacy. RESULTS: P-EVs inherited the adhesive proteins and natural targeting ability to injured vasculature of platelets and retained the pro-angiogenic potential of EVs. In the MI/R model, P-EVs preferentially accumulated in the injured endothelium of the ischemic hearts and enhanced the angiogenesis potency of EVs. CONCLUSIONS: This engineering strategy to modify pre-isolated EVs with platelet membranes by membrane fusion bestows EVs with the targeting ability of platelets and offers an exciting opportunity to design other targeted EVs fused with cell membranes from different sources for therapeutic angiogenesis.

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