Analysis and Validation of Critical Signatures and Immune Cell Infiltration Characteristics in Doxorubicin-Induced Cardiotoxicity by Integrating Bioinformatics and Machine Learning.

Purpose: Doxorubicin-induced cardiotoxicity (DIC) is a severe side reaction in cancer chemotherapy that greatly impacts the well-being of cancer patients. Currently, there is still an insufficiency of effective and reliable biomarkers in the field of clinical practice for the early detection of DIC. This study aimed to determine and validate the potential diagnostic and predictive values of critical signatures in DIC. Methods: We obtained high-throughput sequencing data from the GEO database and performed data analysis and visualization using R software, GO, KEGG and Cytoscape. Machine learning methods and weighted gene coexpression network (WGCNA) were used to identify key genes for diagnostic model construction. Receiver operating characteristic (ROC) analysis and a nomogram were used to assess their diagnostic values. A multiregulatory network was built to reveal the possible regulatory relationships of critical signatures. Cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) analysis was used to investigate differential immune cell infiltration. Additionally, a cell and animal model were constructed to investigate the relationship between the identified genes and DIC. Results: Among the 3713 differentially expressed genes, three key genes (CSGALNACT1, ZNF296 and FANCB) were identified. A nomogram and ROC curves based on three key genes showed excellent diagnostic predictive performance. The regulatory network analysis showed that the TFs CREB1, EP300, FLI1, FOXA1, MAX, and MAZ modulated three key genes. An analysis of immune cell infiltration indicated that many immune cells (activated NK cells, M0 macrophages, activated dendritic cells and neutrophils) might be related to the progression of DIC. Furthermore, there may be various degrees of correlation between the three critical signatures and immune cells. RT‒qPCR demonstrated that the mRNA expression of CSGALNACT1 and ZNF296 was significantly upregulated, while FANCB was significantly downregulated in DOX-treated cardiomyocytes in vitro and in vivo. Conclusion: Our study suggested that the differential expression of CSGALNACT1, ZNF296 and FANCB is associated with cardiotoxicity and is also involved in immune cell infiltration in DIC. They might be potential biomarkers for the early occurrence of DIC.

The TFPI2-PPARγ axis induces M2 polarization and inhibits fibroblast activation to promote recovery from post-myocardial infarction in diabetic mice.

BACKGROUND: Diabetes mellitus is one of the causes of poor ventricular remodelling and poor cardiac recovery after myocardial infarction (MI). We previously reported that tissue factor pathway inhibitor-2 (TFPI2) was downregulated in response to hyperglycaemia and that it played a pivotal role in extracellular matrix (ECM) degradation and cell migration. Nonetheless, the function and mechanism of TFPI2 in post-MI remodelling under diabetic conditions remain unclear. Therefore, in the present study, we investigated the role of TFPI2 in post-MI effects in a diabetic mouse model. RESULTS: TFPI2 expression was markedly decreased in the infarcted myocardium of diabetic MI mice compared with that in non-diabetic mice. TFPI2 knockdown in the MI mouse model promoted fibroblast activation and migration as well as matrix metalloproteinase (MMP) expression, leading to disproportionate fibrosis remodelling and poor cardiac recovery. TFPI2 silencing promoted pro-inflammatory M1 macrophage polarization, which is consistent with the results of TFPI2 downregulation and M1 polarization under diabetic conditions. In contrast, TFPI2 overexpression in diabetic MI mice protected against adverse cardiac remodelling and functional deterioration. TFPI2 overexpression also inhibited MMP2 and MMP9 expression and attenuated fibroblast activation and migration, as well as excessive collagen production, in the infarcted myocardium of diabetic mice. TFPI2 promoted an earlier phenotype transition of pro-inflammatory M1 macrophages to reparative M2 macrophages via activation of peroxisome proliferator-activated receptor gamma. CONCLUSIONS: This study highlights TFPI2 as a promising therapeutic target for early resolution of post-MI inflammation and disproportionate ECM remodelling under diabetic conditions.

Temporal Trends and Early Outcomes of Transcatheter versus Surgical Mitral Valve Repair in Atrial Fibrillation Patients.

Objectives: To study trends of utilization, in-hospital outcomes, and short outcomes in patients undergoing transcatheter mitral valve repair (TMVR) vs. surgical mitral valve repair (SMVR) in atrial fibrillation (AF). Background: TMVR is a treatment option in inoperable or high-risk patients with mitral regurgitation (MR). AF is a common comorbidity of MR. Data comparing between TMVR and SMVR in MR patients with AF is lacking. Methods: The National Readmission Database from 2016 to 2019 was utilized to identify hospitalizations undergoing TMVR or SMVR with AF. Outcomes of interest included mortality, postoperative complications, length of stay, and 30-day readmission rate. Results: A total of 9,195 patients underwent TMVR and 16,972 patients underwent SMVR with AF; the number of AF undergoing TMVR was increasing from 1,342 in 2016 to 4,215 in 2019 and SMVR. The incidence of in-hospital mortality decreased from 2.6% in 2016 to 1.8% in 2019. We identified length of stay>5 days, dyslipidemia, cerebrovascular disease, heart failure with reduced ejection fraction, and urgent/emergent admissions as independent risk factors for in-hospital mortality. After matching, we included 4,680 patients in each group; the in-hospital death, transfusion, acute kidney injury, sepsis, stroke, and mechanical ventilation were lower in TMVR compared with SMVR. TMVR was associated with a similar rate of all-cause readmission at 30 days compared with SMVR. Conclusion: Patients with AF receiving TMVR have been increasing along with progressive improvement in in-hospital death and length of stay. Compared to SMVR, AF patients receiving TMVR had a lower rate of in-hospital death and postoperative complications.

Transcatheter versus surgical aortic valve replacement in patients with aortic regurgitation: A propensity-matched analysis.

This study aimed to analyze in-hospital and early-to-interim outcomes of pure aortic regurgitation (AR) using transcatheter aortic valve replacement (TAVR) vs. surgical aortic valve replacement (SAVR). Background: Few studies have discussed and compared the safety and short-term prognosis of TAVR and SAVR in pure AR patients. As such, we looked to the National Readmissions Database (NRD) for records between 2016 and 2019 in order to identify patients diagnosed with pure AR who underwent SAVR or TAVR. We used the propensity score matching to minimize disparities between two groups. We included 23,276 pure AR patients: 1983 (8.5%) who underwent TAVR and 21,293 (91.5%) who underwent SAVR. We found 1820 matched pairs using propensity score matching. In the matching cohort, TAVR was associated with a low risk of in-hospital mortality. Although TAVR had lower incidences of 30-day all-cause readmission (hazard ratio (HR):0.73, 95% confidence interval (CI): 0.61-0.87; P < 0.01) and 6-month all-cause readmission (HR: 0.81, 95% CI: 0.67-0.97; P = 0.03), while TAVR had high incidences of 30-day permanent pacemaker implantation incidence (HR: 3.54, 95% CI: 1.62-7.74; P < 0.01) and 6-month permanent pacemaker implantation incidence (HR: 4.12, 95% CI: 1.17-14.4; P = 0.03).In conclusion, TAVR and SAVR had similar risks of hospital death and lower rates of 30-day and 6-month all-cause and cardiovascular readmission. But TAVR had a higher risk of permanent pacemaker implantation than SAVR in AR patients, suggesting that TAVR can be performed safely in pure AR patients.

Evaluation of metoprolol standard dosing pathway in Chinese patients with acute coronary syndrome: a prospective multicenter single-arm interventional study.

OBJECTIVE: To evaluate the feasibility and tolerability of metoprolol standard dosing pathway (MSDP) in Chinese patients with acute coronary syndrome (ACS). METHODS: In this multicenter, prospective, open label, single-arm and interventional study that was conducted from February 2018 to April 2019 in fifteen Chinese hospitals. A total of 998 hospitalized patients aged ≥ 18 years and diagnosed with ACS were included. The MSDP was applied to all eligible ACS patients based on the standard treatment recommended by international guidelines. The primary endpoint was the percentage of patients achieving the target dose at discharge (V2). The secondary endpoints included the heart rate and blood pressure at V2 and four weeks after discharge (V4), and percentage of patients experiencing bradycardia (heart rate < 50 beats/min), hypotension (blood pressure < 90/60 mmHg) and transient cardiac dysfunction at V2 and V4. RESULTS: Of the 998 patients, 29.46% of patients achieved the target dose (≥ 95 mg/d) at V2. The total population was divided into two groups: target group (patients achieving the target dose at V2) and non-target group (patients not achieving the target dose at V2). There was significant difference in the reduction of heart rate from baseline to discharge in the two groups (-4.97 ± 11.90 beats/min vs. -2.70 ± 9.47 beats/min, P = 0.034). There was no significant difference in the proportion of bradycardia that occurred in the two groups at V2 (0 vs. 0, P = 1.000) and V4 (0.81% vs. 0.33%, P = 0.715). There was no significant difference in the proportion of hypotension between the two groups at V2 (0.004% vs. 0.004%, P = 1.000) and V4 (0 vs. 0.005%, P = 0.560). No transient cardiac dysfunction occurred in two groups during the study. A total of five adverse events (1.70%) and one serious adverse event (0.34%) were related to the pathway in target group. CONCLUSIONS: In Chinese ACS patients, the feasibility and tolerability of the MSDP have been proved to be acceptable.

Association of age at menarche with valvular heart disease: An analysis based on electronic health record (CREAT2109).

Background: The association between age at menarche and coronary heart disease has been reported, but the association between age at menarche and valvular heart disease (VHD) has not been described. We aimed to examine the association between age at menarche and VHD. Methods: By collecting data from four medical centers of the Affiliated Hospital of Qingdao University (QUAH) from January 1, 2016, to December 31, 2020, we sampled 105,707 inpatients. The main outcome of this study was newly diagnosed VHD, which was diagnosed based on ICD-10 coding, and the exposure factor was age at menarche, which was accessed through the electronic health records. We used logistic regression model to investigate the association between age at menarche and VHD. Results: In this sample (mean age 55.31 ± 13.63 years), the mean age at menarche was 15. Compared with women with age at menarche 14-15 years, the odds ratio of VHD in women with age at menarche ≤13, 16-17, and ≥18 years was 0.68 (95% CI 0.57-0.81), 1.22 (95% CI 1.08-1.38), and 1.31 (95% CI 1.13-1.52), respectively (P for all < 0.001). By restricting cubic splines, we found that later menarche was associated with increased odds of VHD (P < 0.001). Furthermore, in subgroup analysis of different etiologies, the similar trend persisted for non-rheumatic VHD. Conclusions: In this large inpatient sample, later menarche was associated with higher risk of VHD.

Efficacy and safety profile of angiotensin receptor neprilysin inhibitors in the management of heart failure: a systematic review and meta-analysis of randomized controlled trials.

Several guidelines have recommended the use of angiotensin receptor neprilysin inhibitors (ARNIs) as replacement for angiotensin-converting enzyme inhibitors in the management of heart failure. Till date, there are no reviews done that comprehensively cover different aspects of efficacy and safety parameters. Hence, we have performed a comprehensive systematic review and meta-analysis on role of ARNIs for the management of heart failure patients. Searches were done in Embase, Scopus, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, PubMed Central, Cochrane Library, MEDLINE, Google Scholar, ScienceDirect and Clinicaltrials.gov until June 2022. Risk of bias assessment was done with Cochrane's risk of bias tool. Meta-analysis was carried out using random-effects model. Pooled standardized mean difference (SMD)/mean difference (MD) and/or risk ratio (RR) with 95% confidence intervals (CIs) was reported. In total, we analysed 34 studies, with almost all of them had a high risk of bias. Pooled RR was 0.88 (95% CI: 0.82-0.95) for all-cause mortality, 0.84 (95% CI: 0.77-0.92) for cardiovascular mortality and 0.78 (95% CI: 0.70-0.87) for hospitalization. Pooled MD was 3.74 (95% CI: 1.93-5.55) for left ventricular ejection fraction, -2.16 (95% CI: -3.58 to -0.74) for left atrial volume index, -3.80 (95% CI: -6.60 to -1.00) for left ventricular end-diastolic dimension and -1.16 (95% CI: -1.98 to -0.35) for E/E' ratio. Regarding adverse events, pooled RR was 1.55 (95% CI: 1.31-1.85) for symptomatic hypotension, 0.93 (95% CI: 0.78-1.11) for worsening renal function, 1.09 (95% CI: 0.94-1.26) for hyperkalaemia and 1.29 (95% CI: 0.67-2.50) for angioedema. ARNIs had beneficial efficacy and safety profile on the management of heart failure especially patients with reduced ejection fraction.

Gender Differences in Age-Stratified Early Outcomes in Patients With Transcatheter Aortic Valve Implantation.

Few researchers have discussed the differences in gender between the age groups of patients who underwent transcatheter aortic valve implantation (TAVI). We searched the National Readmissions Database from 2012 to 2019 to identify adults who underwent TAVI. We studied hospital outcomes and short- to medium-term outcomes by age stratification (18 to 59, 60 to 69, 70 to 79, and 80 to 90 years) after TAVI and categorized by gender. We included 147,481 patients who underwent TAVI, and 54,802 pairs were matched using propensity score matching separately for each age group. Compared with men, women in all age groups had a similar rate of hospital death. Except the 18- to 59-year-old groups, female patients were less likely to undergo permanent pacemaker implantation and transfusion. Records of readmission at 30 days and 6 months were used as the follow-up outcome according to the presence or absence of readmission. Major adverse cardiovascular events (MACEs) were a composite of cardiovascular readmission, all-cause mortality during readmission, and stroke readmission. At the 30-day follow-up visit, there was no difference in the all-cause readmission and MACE between women and men in any group. At the 6-month follow-up visit, women in the 70- to 79-year-old and 80- to 90-year-old groups had a high risk of all-cause readmission. In conclusion, we reported that female patients have similar in-hospital death rates to male patients who underwent TAVI. During the 30-day follow-up visit, the all-cause readmission and MACE were not different in all age groups between men and women. At 6 months, women in the 70- to 79-year-old and 80- to 90-year-old groups had a higher risk of all-cause readmission.

Protective effect of ischaemic postconditioning combined with nicorandil on myocardial ischaemia‒reperfusion injury in diabetic rats.

BACKGROUND: The diabetic heart exhibits a high sensitivity to ischaemia/reperfusion (I/R) injury. Diabetes mellitus (DM) can affect the efficacy of cardioprotective interventions and reduce the therapeutic potential of existing treatment options. This study aimed to investigate the feasibility of shifting from monotherapy to combination therapy in diabetic myocardial I/R injury. METHODS: 6-8 week rats were randomized into 10 groups: sham, I/R, ischaemia postconditioning (I-Post), nicorandil (Nic), combination therapy (I-Post + Nic), DM sham, DM I/R, DM I-Post, DM Nic and DM I-Post + Nic. The extent of myocardial injury was clarified by measuring CK-MB and NO levels in plasma, ROS content in myocardial tissues, and TTC/Evans Blue staining to assess the area of myocardial infarction. Pathological staining of cardiac tissue sections were performed to clarify the structural changes in myocardial histopathology. Finally, Western blotting was performed to detect the phosphorylation levels of some key proteins in the PI3K/Akt signalling pathway in myocardial tissues. RESULTS: We confirms that myocardial injury in diabetic I/R rats remained at a high level after treatment with I-Post or nicorandil alone. I-Post combined with nicorandil showed better therapeutic effects in diabetic I/R rats, and the combined treatment further reduced the area of myocardial injury in diabetic I/R rats compared with I-Post or nicorandil treatment alone (P < 0.001), as well as the levels of the myocardial injury markers CK-MB and ROS (P < 0.001); it also significantly increased plasma NO levels. Pathological staining also showed that diabetic rats benefited significantly from the combination therapy. Further mechanistic studies confirmed this finding. The protein phosphorylation levels of PI3K/Akt signalling pathway in the heart tissue of diabetic I/R rats were significantly higher after the combination treatment than after one treatment alone (all P < 0.05). CONCLUSION: I-Post combined with nicorandil treatment maintains effective cardioprotection against diabetic myocardial I/R injury by activating the PI3K/Akt signalling pathway.

Superassembled Hierarchical Asymmetric Magnetic Mesoporous Nanorobots Driven by Smart Confined Catalytic Degradation.

Invited for the cover of this issue is the group of Biao Kong at Fudan University. The image depicts a hierarchical asymmetric magnetic mesoporous hollow nanorobot that combines the functionalities of magnetic responsiveness, reusability, sustainable motility and durable motion, showing excellent pollutant degradation capability. Read the full text of the article at. 10.1002/chem.202200307.

Superassembled Hierarchical Asymmetric Magnetic Mesoporous Nanorobots Driven by Smart Confined Catalytic Degradation.

Micro/nanoscale robotics has received great attention in many important fields. However, it is still a great challenge to construct nanorobots simultaneously possessing multifunctionality, well-controlled directionality, and fast and durable motion as well as fully compatible and biodegradable components. Here, a hierarchical, asymmetric, hollow, catalytic, magnetic, and mesoporous nanorobot has been fabricated through a multistep interfacial superassembly strategy. The multilayer composites consist of hollow silica nanoflasks sequentially coated with a highly magnetic responsive Fe3 O4 layer, a mesoporous silica layer with homogeneous vertical channels, and a layer of catalytic gold nanoparticles on both the inner and outer surfaces. Furthermore, para-nitrophenol was used as a model pollutant to trigger self-motility of the nanoflasks by confined catalytic degradation (CCD). We found that the bottleneck morphology and mesoporous surface both improved the catalytic nanoparticle loading capability and CCD effect, thus enabling efficient self-motility and a durable movement capacity of ∼100 h. In addition, the catalytic performance was improved by 180 % compared with that of solid spherical nanoparticles.

Increased ratio of sST2/LVMI predicted cardiovascular mortality and heart failure rehospitalization in heart failure with reduced ejection fraction patients: a prospective cohort study.

BACKGROUND: Inflammation is one of the principal triggering mechanisms for left ventricular fibrosis and remodeling in heart failure, leading to adverse clinical outcomes. Soluble suppression of tumorigenicity 2 (sST2), a member of the interleukin-1 receptor family, is assumed to play a significant role in the fibrotic response to inflammation. Left ventricular mass index (LVMI) is a parameter of the prefibrotic inflammatory phase of heart failure preceding remodeling. The present study aimed to investigate the prognostic value of the sST2/LVMI ratio in heart failure with reduced ejection fraction. METHODS: This was a prospective cohort study. A total of 45 consecutive patients with heart failure with reduced ejection fraction, treated between September 2015 and December 2016, were enrolled. The sST2/LVMI ratio was measured at baseline. The primary endpoint was a composite of cardiovascular mortality and readmission for heart failure. The prognostic impact of the sST2/LVMI ratio was evaluated using a multivariable Cox proportional hazards regression model. RESULTS: Forty-five patients were enrolled in this study. Their average age was 48 ± 14 years, and approximately 20% of them were men. Patients were followed for 9 months, during which the primary outcome occurred in 15 patients. Kaplan-Meier analysis showed that patients with a high sST2/LVMI ratio (≥ 0.39) had shorter event-free survival than those with intermediate (between 0.39 and 0.24) and low ratios (< 0.24) (log-rank, P = 0.022). The fully adjusted multivariable Cox regression analysis showed that the sST2/LVMI ratio was positively associated with the composite outcome in patients with heart failure with reduced ejection fraction after adjusting for confounders (hazard ratio 1.64, 95% confidence interval 1.06 to 2.54). By subgroup analysis, a stronger association was found with age between 40 and 55 years, systolic blood pressure < 115 or ≥ 129 mmHg, diastolic blood pressure < 74 mmHg, hematocrit < 44.5%, and interventricular septum thickness ≥ 8.5 mm. CONCLUSION: In patients with heart failure with reduced ejection fraction, the relationship between the sST2/LVMI ratio and the composite outcome was linear. A higher baseline ratio of sST2/LVMI was associated with an increased risk of cardiovascular mortality and heart failure rehospitalization in the short-term follow-up.

TRIM25 Rescues Against Doxorubicin-Induced Pyroptosis Through Promoting NLRP1 Ubiquitination.

Doxorubicin (DOX) is an antineoplastic agent that is widely employed in carcinomas, but it can cause cardiotoxicity in clinic. TRIM25 has E3 ubiquitin ligase activities and can ubiquitinate its target proteins. The role of TRIM25 in DOX-induced cardiotoxicity remains unknown. In this study, our results showed that DOX induced pyroptosis of H9c2 cells by TUNEL staining and Western blot assay. Interestingly, TRIM25 was downregulated in DOX-treated H9c2 cells in a time- and dose-dependent manner. TRIM25 attenuated DOX-induced pyroptosis of H9c2 cells. Furthermore, in vitro ubiquitination assay proved that TRIM25 decreased the stability of NLRP1 via promoting the ubiquitination of NLRP1. The rescue experiments confirmed that TRIM25 inhibited DOX-induced H9c2 cells pyroptosis by regulating NLRP1 stability. Animal experiments demonstrated that overexpression of TRIM25 attenuated DOX-induced cardiomyocyte pyroptosis in rats. In summary, TRIM25 exerts its cardioprotective effects by promoting the ubiquitination of NLRP1 in DOX-induced cardiomyocyte pyroptosis, which provides a novel therapeutic strategy for DOX-induced cardiotoxicity.

Prediction model of in-hospital mortality in intensive care unit patients with heart failure: machine learning-based, retrospective analysis of the MIMIC-III database.

OBJECTIVE: The predictors of in-hospital mortality for intensive care units (ICUs)-admitted heart failure (HF) patients remain poorly characterised. We aimed to develop and validate a prediction model for all-cause in-hospital mortality among ICU-admitted HF patients. DESIGN: A retrospective cohort study. SETTING AND PARTICIPANTS: Data were extracted from the Medical Information Mart for Intensive Care (MIMIC-III) database. Data on 1177 heart failure patients were analysed. METHODS: Patients meeting the inclusion criteria were identified from the MIMIC-III database and randomly divided into derivation (n=825, 70%) and a validation (n=352, 30%) group. Independent risk factors for in-hospital mortality were screened using the extreme gradient boosting (XGBoost) and the least absolute shrinkage and selection operator (LASSO) regression models in the derivation sample. Multivariate logistic regression analysis was used to build prediction models in derivation group, and then validated in validation cohort. Discrimination, calibration and clinical usefulness of the predicting model were assessed using the C-index, calibration plot and decision curve analysis. After pairwise comparison, the best performing model was chosen to build a nomogram according to the regression coefficients. RESULTS: Among the 1177 admissions, in-hospital mortality was 13.52%. In both groups, the XGBoost, LASSO regression and Get With the Guidelines-Heart Failure (GWTG-HF) risk score models showed acceptable discrimination. The XGBoost and LASSO regression models also showed good calibration. In pairwise comparison, the prediction effectiveness was higher with the XGBoost and LASSO regression models than with the GWTG-HF risk score model (p<0.05). The XGBoost model was chosen as our final model for its more concise and wider net benefit threshold probability range and was presented as the nomogram. CONCLUSIONS: Our nomogram enabled good prediction of in-hospital mortality in ICU-admitted HF patients, which may help clinical decision-making for such patients.

Long Non-coding RNA PEBP1P2 Suppresses Proliferative VSMCs Phenotypic Switching and Proliferation in Atherosclerosis.

Long non-coding RNAs (lncRNAs) play a crucial role in the growth of vascular smooth muscle cells (VSMCs), the dysfunction of which is closely associated with the initiation and progression of cardiovascular diseases (CVDs). Abnormal phenotypic switching and proliferation of VSMCs constitute a significant event in the progression of atherosclerosis. The present study identified a novel lncRNA, PEBP1P2, which serves as a valuable regulator of VSMCs in phenotypic transformation and proliferation. The expression of PEBP1P2 was remarkably decreased in proliferating VSMCs and pathological arteries when using a balloon injury model of rats. Furthermore, we found that PEBP1P2 represses proliferation, migration, and dedifferentiation during phenotype switching in VSMCs induced by platelet-derived growth factor BB (PDGF-BB). Mechanistically, cyclin-dependent kinase 9 (CDK9) was confirmed to be the direct target of PEBP1P2, which was proven to mediate phenotypic switching and proliferation of VSMCs and was rescued by PEBP1P2. Then, we explored the clinical significance, as we observed the decreased expression of PEBP1P2 in the serum of coronary heart disease (CHD) patients and human advanced carotid atherosclerotic plaques. Finally, PEBP1P2 overexpression distinctly suppressed neointima formation and VSMC phenotypic switching in vivo. Taken together, PEBP1P2 inhibits proliferation and migration in VSMCs by directly binding to CDK9, implying that it may be a promising therapeutic target for the treatment of proliferative vascular diseases.

Biointerface topography regulates phenotypic switching and cell apoptosis in vascular smooth muscle cells.

BACKGROUND: In-stent restenosis (ISR) is a complex disease that occurs after coronary stenting procedures. The development of quality materials and improvement of our understanding on significant factors regulating ISR are essential for enhancing prognosis. Vascular smooth muscle cells (VSMCs) are the main constituent cells of blood vessel walls, and dysfunction of VMSCs can exacerbate ISR. Accordingly, in this study, we explored the influence of wrinkled material topography on the biological functions of VSMCs. METHODS: Polydimethylsiloxane with a wrinkled topography was synthesized using elastomer base and crosslinking and observed by atomic force microscopy. VSMC proliferation, apoptosis, and morphology were determined by Cell Counting Kit-8 assays, fluorescence-assisted cell sorting, and phalloidin staining. α-Smooth muscle actin (α-SMA), major histocompatibility complex (MHC), and calponin 1 (CNN-1) expression levels were measured by quantitative real-time polymerase chain reaction and western blotting. Moreover, p53 and cleaved caspase-3 expression levels were evaluated by western blotting in VSMCs to assess apoptotic induction. RESULTS: Surface topographies were not associated with a clear orientation or elongation of VSMCs. The number of cells was increased on wrinkled surfaces (0.7 µm in amplitude, and 3 µm in wavelength [W3]) compared with that on other surfaces, contributing to continuously increased cell proliferation. Moreover, interactions of VSMCs with the W3 surface suppressed phenotypic switching, resulting in ISR via regulation of α-SMA, calponin-1, and SM-MHC expression. The surface with an amplitude of 0.05 µm and a wavelength of 0.5 µm (W0.5) promoted apoptosis by inducing caspase 3 and p53 activities. CONCLUSION: Introduction of aligned topographies on biomaterial scaffolds could provide physical cues to modulate VSMC responses for engineering vascular constructs. Materials with wrinkled topographies could have applications in the development of stents to reduce ISR.