Understanding the mental health impacts of biological disasters: Lessons from Taiwan's experience with COVID-19.

Biological disasters pose a growing challenge in the 21st century, significantly impacting global society. Taiwan has experienced such disasters, resulting in long-term consequences like loss of life, trauma, economic decline, and societal disruptions. Post-disaster, mental health issues such as fear, anxiety, depression, post-traumatic stress disorder (PTSD), and stress surge, accompanied by increased suicide rates. The Coronavirus disease 2019 (COVID-19) (also called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) pandemic, recognized as a biological disaster, triggered lockdowns and quarantines in Taiwan, causing lifestyle changes, economic recession, and so on. These shifts may elevate uncertainty about the future, intensifying mental stress and leading to a rise in various mental illnesses. This article reviews mental health studies conducted in Taiwan during the pandemic, emphasizing the need to integrate this research for future preparedness and interventions regarding the mental health impacts of biological disasters, including COVID-19. Further research is essential to explore long-term effects, interventions, and generalizability.

FGF9, a Potent Mitogen, Is a New Ligand for Integrin αvß3, and the FGF9 Mutant Defective in Integrin Binding Acts as an Antagonist.

FGF9 is a potent mitogen and survival factor, but FGF9 protein levels are generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in cancer. However, the mechanism of FGF9 action has not been fully established. Previous studies showed that FGF1 and FGF2 directly bind to integrin αvß3, and this interaction is critical for signaling functions (FGF-integrin crosstalk). FGF1 and FGF2 mutants defective in integrin binding were defective in signaling, whereas the mutants still bound to FGFR suppressed angiogenesis and tumor growth, indicating that they act as antagonists. We hypothesize that FGF9 requires direct integrin binding for signaling. Here, we show that docking simulation of the interaction between FGF9 and αvß3 predicted that FGF9 binds to the classical ligand-binding site of αvß3. We show that FGF9 bound to integrin αvß3 and generated FGF9 mutants in the predicted integrin-binding interface. An FGF9 mutant (R108E) was defective in integrin binding, activating FRS2α and ERK1/2, inducing DNA synthesis, cancer cell migration, and invasion in vitro. R108E suppressed DNA synthesis and activation of FRS2α and ERK1/2 induced by WT FGF9 (dominant-negative effect). These findings indicate that FGF9 requires direct integrin binding for signaling and that R108E has potential as an antagonist to FGF9 signaling.

FGF9, a potent mitogen, is a new ligand for integrin αvß3, and the FGF9 mutant defective in integrin binding acts as an antagonist.

FGF9 is a potent mitogen and survival factor, but FGF9 protein level is generally low and restricted to a few adult organs. Aberrant expression of FGF9 usually results in cancer. However, the mechanism of FGF9 action has not been fully established. Previous studies showed that FGF1 and FGF2 directly bind to integrin αvß3 and this interaction is critical for signaling functions (FGF-integrin crosstalk). FGF1 and FGF2 mutants defective in integrin binding were defective in signaling, whereas the mutants still bound to FGFR, and suppressed angiogenesis and tumor growth, indicating that they act as antagonists. We hypothesize that FGF9 requires direct integrin binding for signaling. Here we show that docking simulation of interaction between FGF9 and αvß3 predicted that FGF9 binds to the classical ligand-binding site of αvß3. We showed that FGF9 actually bound to integrin αvß3, and generated an FGF9 mutants in the predicted integrin-binding interface. An FGF9 mutant (R108E) was defective in integrin binding, activating FRS2α and ERK1/2, inducing DNA synthesis, cancer cell migration, and invasion in vitro. R108E suppressed DNA synthesis induced by WT FGF9 and suppressed DNA synthesis and activation of FRS2α and ERK1/2 induced by WT FGF9 (dominant-negative effect). These findings indicate that FGF9 requires direct integrin binding for signaling and that R108E has potential as an antagonist to FGF9 signaling.

Effect of the simulated half leaf width of a multileaf collimator on volumetric modulated arc therapy plan quality in hippocampal avoidance whole-brain radiotherapy.

PURPOSE: Whole-brain radiotherapy (WBRT) is commonly used in patients with multiple brain metastases. Compared with conventional WBRT, hippocampal avoidance WBRT (HA-WBRT) more favorably preserves cognitive function and the quality of life. The hippocampal volume is considerably small (approximately 3.3 cm3 ). Therefore, downsizing the leaf width of a multileaf collimator (MLC) may provide higher spatial resolution and better plan quality. Volumetric modulated arc therapy (VMAT) could simulate the half MLC leaf width through couch shifting between arcs. This study investigated changes in VMAT quality for HA-WBRT with a simulated fine MLC leaf width. METHODS: We included 18 patients with brain metastasis. All target and avoidance structures were contoured by an experienced radiation oncologist. The prescribed dose was 30 Gy in 10 fractions. For each patient, three different treatment plans were generated for comparison: VMAT with couch-shift, VMAT without couch-shift, and TomoTherapy. All treatment plans fulfilled Radiation Therapy Oncology Group (RTOG) 0933 criteria for HA-WBRT. The Wilcoxon paired signed-rank test was used to compare different treatment plans. RESULTS: VMAT with couch-shift had the better average conformity index (0.823) with statistically significant difference compared to VMAT without couch-shift (0.810). VMAT with couch-shift (0.219) had a more favorable average homogeneity index (HI) than did VMAT without couch-shift (0.230), although the difference was not significant. TomoTherapy had an optimal average HI of 0.070. In terms of the hippocampus, all three treatment plans met the RTOG 0933 criteria. VMAT with couch-shift had a lower average Dmax (15.2 Gy) than did VMAT without couch-shift (15.3 Gy, p = 0.071) and TomoTherapy (15.5 Gy, p = 0.133). The average D100% of hippocampus was the same for both VMAT with and without couch-shift (8.5 Gy); however, TomoTherapy had a lower average D100% value of 7.9 Gy. The treatment delivery time was similar between VMAT with and without couch-shift (average, 375.0 and 369.6 s, respectively). TomoTherapy required a long average delivery time of 1489.9 s. CONCLUSION: The plan quality of VMAT for HA-WBRT was improved by using the couch-shift technique to simulate the half MLC leaf width. However, the improvement was not statistically significant except conformity index. The downsizing effect decreased with the use of the sophisticated grade of VMAT. TomoTherapy offered superior plan quality but required the longest delivery time.

Dosimetric comparison of helical tomotherapy, volumetric-modulated arc therapy, intensity-modulated radiotherapy, and field-in-field technique for synchronous bilateral breast cancer.

PURPOSE: To compare the dosimetric characteristics of helical tomotherapy (HT), volumetric-modulated arc therapy (VMAT), intensity-modulated radiotherapy (IMRT), and tangential field-in-field technique (FIF) for the treatment of synchronous bilateral breast cancer (SBBC). METHODS AND MATERIALS: Ten patients with early-stage unilateral breast cancer were selected for simulating the patients with SBBC in this retrospective analysis. Treatment plans with HT, VMAT, IMRT, and FIF were generated for each patient with a total dose of 50.4 Gy in 28 fractions to the target. Plan quality, namely conformity index (CI), homogeneity index (HI), dose-volume statistics of organs at risk (OARs), and beam-on time (BOT), were evaluated. RESULTS: HT plans showed a lower mean heart dose (3.53 ± 0.31Gy) compared with the other plans (VMAT = 5.6 ± 1.36 Gy, IMRT = 3.80 ± 0.76 Gy, and FIF = 4.84 ± 2.13 Gy). Moreover, HT plans showed a significantly lower mean lung dose (p < 0.01) compared with the other plans: mean right lung doses were 6.81 ± 0.67, 10.32 ± 1.04, 9.07 ± 1.21, and 10.03 ± 1.22 Gy and mean left lung doses were 6.33 ± 0.87, 8.82 ± 0.91, 7.84 ± 1.07, and 8.64 ± 0.99 Gy for HT, VMAT, IMRT, and FIF plans, respectively. The mean dose to the left anterior descending artery was significantly lower in HT plans (p < 0.01) than in the other plans: HT = 19.41 ± 0.51 Gy, VMAT = 25.77 ± 7.23 Gy, IMRT = 27.87 ± 6.48 Gy, and FIF = 30.95 ± 10.17 Gy. FIF plans showed a worse CI and HI compared with the other plans. VMAT plans showed shorter BOT (average, 3.9 ± 0.2 minutes) than did HT (average, 11.0 ± 3.0 minutes), IMRT (average, 6.1 ± 0.5 minutes), and FIF (average, 4.6 ± 0.7 minutes) plans. CONCLUSIONS: In a dosimetric comparison for SBBC, HT provided the most favorable dose sparing of OARs. However, HT with longer BOT may increase patient discomfort and treatment uncertainty. VMAT enabled shorter BOT with acceptable doses to OARs and had a better CI than did FIF and IMRT.

Variations in dosimetric distribution and plan complexity with collimator angles in hypofractionated volumetric arc radiotherapy for treating prostate cancer.

PURPOSE: Hypofractionated radiotherapy can reduce treatment durations and produce effects identical to those of conventionally fractionated radiotherapy for treating prostate cancer. Volumetric arc radiotherapy (VMAT) can decrease the treatment machine monitor units (MUs). Previous studies have shown that VMAT with multileaf collimator (MLC) rotation exhibits better target dose distribution. Thus, VMAT with MLC rotation warrants further investigation. METHODS AND MATERIALS: Ten patients with prostate cancer were included in this study. The prostate gland and seminal vesicle received 68.75 and 55 Gy, respectively, in 25 fractions. A dual-arc VMAT plan with a collimator angle of 0° was generated and the same constraints were used to reoptimize VMAT plans with different collimator angles. The conformity index (CI), homogeneity index (HI), gradient index (GI), normalized dose contrast (NDC), MU, and modulation complexity score (MCSV ) of the target were analyzed. The dose-volume histogram of the adjacent organs was analyzed. A Wilcoxon signed-rank test was used to compare different collimator angles. RESULTS: Optimum values of CI, HI, and MCSV were obtained with a collimator angle of 45°. The optimum values of GI, and NDC were observed with a collimator angle of 0°. In the rectum, the highest values of maximum dose and volume receiving 60 Gy (V60 Gy ) were obtained with a collimator angle of 0°, and the lowest value of mean dose (Dmean ) was obtained with a collimator angle of 45°. In the bladder, high values of Dmean were obtained with collimator angles of 75° and 90°. In the rectum and bladder, the values of V60 Gy obtained with the other tested angles were not significantly higher than those obtained with an angle of 0°. CONCLUSION: This study found that MLC rotation affects VMAT plan complexity and dosimetric distribution. A collimator angle of 45° exhibited the optimal values of CI, HI, and MCSv among all the tested collimator angles. Late side effects of the rectum and bladder are associated with high-dose volumes by previous studies. MLC rotation did not have statistically significantly higher values of V60 Gy in the rectum and bladder than did the 0° angle. We thought a collimator angle of 45° was an optimal angle for the prostate VMAT treatment plan. The findings can serve as a guide for collimator angle selection in prostate hypofractionated VMAT planning.

Direct integrin binding to insulin-like growth factor-2 through the C-domain is required for insulin-like growth factor receptor type 1 (IGF1R) signaling.

We have reported that integrins crosstalk with growth factors through direct binding to growth factors (e.g., fibroblast growth factor-1, insulin-like growth factor 1 (IGF1), neuregulin-1, fractalkine) and subsequent ternary complex formation with cognate receptor [e.g., integrin/IGF1/IGF1 receptor (IGF1R)]. IGF1 and IGF2 are overexpressed in cancer and major therapeutic targets. We previously reported that IGF1 binds to integrins ανß3 and α6ß4, and the R36E/R37E mutant in the C-domain of IGF1 is defective integrin binding and signaling functions of IGF1, and acts as an antagonist of IGF1R. We studied if integrins play a role in the signaling functions of IGF2, another member of the IGF family. Here we describe that IGF2 specifically binds to integrins ανß3 and α6ß4, and induced proliferation of CHO cells (IGF1R+) that express ανß3 or α6ß4 (ß3- or α6ß4-CHO cells). Arg residues to Glu at positions 24, 34, 37 and/or 38 in or close to the C-domain of IGF2 play a critical role in binding to integrins and signaling functions. The R24E/R37E/R38E, R34E/R37E/R38E, and R24E/R34E/R37E/R38E mutants were defective in integrin binding and IGF2 signaling. These mutants suppressed proliferation induced by WT IGF2, suggesting that they are dominant-negative antagonists of IGF1R. These results suggest that IGF2 also requires integrin binding for signaling functions, and the IGF2 mutants that cannot bind to integrins act as antagonists of IGF1R. The present study defines the role of the C-domain in integrin binding and signaling.

Association of Changes in Air Quality With Bronchitic Symptoms in Children in California, 1993-2012.

IMPORTANCE: Childhood bronchitic symptoms are significant public and clinical health problems that produce a substantial burden of disease. Ambient air pollutants are important determinants of bronchitis occurrence. OBJECTIVE: To determine whether improvements in ambient air quality in Southern California were associated with reductions in bronchitic symptoms in children. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal study involving 4602 children (age range, 5-18 years) from 3 cohorts was conducted during the 1993-2001, 1996-2004, and 2003-2012 years in 8 Southern California communities. A multilevel logistic model was used to estimate the association of changes in pollution levels with bronchitic symptoms. EXPOSURES: Average concentrations of nitrogen dioxide, ozone, particulate matter with an aerodynamic diameter of less than 10 µm (PM10) and less than 2.5 µm (PM2.5). MAIN OUTCOMES AND MEASURES: Annual age-specific prevalence of bronchitic symptoms during the previous 12 months based on the parent's or child's report of a daily cough for 3 months in a row, congestion or phlegm other than when accompanied by a cold, or bronchitis. RESULTS: The 3 cohorts included a total of 4602 children (mean age at baseline, 8.0 years; 2268 girls [49.3%]; 2081 Hispanic white [45.2%]) who had data from 2 or more annual questionnaires. Among these children, 892 (19.4%) had asthma at age 10 years. For nitrogen dioxide, the odds ratio (OR) for bronchitic symptoms among children with asthma at age 10 years was 0.79 (95% CI, 0.67-0.94) for a median reduction of 4.9 ppb, with absolute decrease in prevalence of 10.1%. For ozone, the OR was 0.66 (95% CI, 0.50-0.86) for a median reduction of 3.6 ppb, with an absolute decrease in prevalence of 16.3%. For PM10, the OR was 0.61 (95% CI, 0.48-0.78) for a median reduction of 5.8 µg/m3, with an absolute decrease in prevalence of 18.7%. For PM2.5, the OR was 0.68 (95% CI, 0.53-0.86) for a median reduction of 6.8 µg/m3, with absolute decrease in prevalence of 15.4%. Among children without asthma (n = 3710), the ORs were 0.84 (95% CI, 0.76-0.92) for nitrogen dioxide; 0.85 (95% CI, 0.74-0.97) for ozone, 0.80 (95% CI, 0.70-0.92) for PM10, and 0.79 (95% CI, 0.69-0.91) for PM2.5; with absolute decrease in prevalence of 1.8% for nitrogen dioxide, 1.7% for ozone, 2.2% for PM10, and 2.3% for PM2.5. The associations were similar or slightly stronger at age 15 years. CONCLUSIONS AND RELEVANCE: Decreases in ambient pollution levels were associated with statistically significant decreases in bronchitic symptoms in children. Although the study design does not establish causality, the findings support potential benefit of air pollution reduction on asthma control.

Comparing treatment plan in all locations of esophageal cancer: volumetric modulated arc therapy versus intensity-modulated radiotherapy.

The aim of this study was to compare treatment plans of volumetric modulated arc therapy (VMAT) with intensity-modulated radiotherapy (IMRT) for all esophageal cancer (EC) tumor locations.This retrospective study from July 2009 to June 2014 included 20 patients with EC who received definitive concurrent chemoradiotherapy with radiation doses >50.4 Gy. Version 9.2 of Pinnacle with SmartArc was used for treatment planning. Dosimetric quality was evaluated based on doses to several organs at risk, including the spinal cord, heart, and lung, over the same coverage of gross tumor volume.In upper thoracic EC, the IMRT treatment plan had a lower lung mean dose (P = 0.0126) and lung V5 (P = 0.0037) compared with VMAT; both techniques had similar coverage of the planning target volumes (PTVs) (P = 0.3575). In middle thoracic EC, a lower lung mean dose (P = 0.0010) and V5 (P = 0.0145), but higher lung V20 (P = 0.0034), spinal cord Dmax (P = 0.0262), and heart mean dose (P = 0.0054), were observed for IMRT compared with VMAT; IMRT provided better PTV coverage. Patients with lower thoracic ECs had a lower lung mean dose (P = 0.0469) and V5 (P = 0.0039), but higher spinal cord Dmax (P = 0.0301) and heart mean dose (P = 0.0020), with IMRT compared with VMAT. PTV coverage was similar (P = 0.0858) for the 2 techniques.IMRT provided a lower mean dose and lung V5 in upper thoracic EC compared with VMAT, but exhibited different advantages and disadvantages in patients with middle or lower thoracic ECs. Thus, choosing different techniques for different EC locations is warranted.

The effects of oxidative stress on the compressive damage thresholds of C2C12 mouse myoblasts: implications for deep tissue injury.

Deep tissue injury (DTI) is a severe kind of pressure ulcers formed by sustained deformation of muscle tissues over bony prominences. As a major clinical issue, DTI affects people with physical disabilities, and is obviously related to the load-bearing capacity of muscle cells in various in vivo conditions. It has been hypothesized that oxidative stress, either induced by reperfusion immediately following tissue unloading or in chronic inflammatory conditions, may affect the cellular capacity against subsequent mechanical damages. In this study, we measured the compressive damage threshold of C2C12 mouse myoblasts with or without pre-treatment of hydrogen peroxide as an oxidative agent to understand how changes in the oxidative environment may contribute to the development of DTI. Spherical indentation was applied onto a layer of agarose gel (3 mm thick) covering a monolayer of C2C12 myoblasts. Cell damage was recognized by using a cell membrane damage assay, propidium iodide. The spatial profile of the measured percentage cell damage was correlated with the radially varying stress field as determined by finite element analysis to estimate the compressive stress threshold for cell damage. Results supported the hypothesis that chronic exposure to high-dosage oxidative stress could compromise the capability of muscle cells to withstand compressive damages, while short exposure to low-dosage oxidative stress could enhance such capability.

A longitudinal cohort study of body mass index and childhood exposure to secondhand tobacco smoke and air pollution: the Southern California Children's Health Study.

BACKGROUND: Childhood body mass index (BMI) and obesity prevalence have been associated with exposure to secondhand smoke (SHS), maternal smoking during pregnancy, and vehicular air pollution. There has been little previous study of joint BMI effects of air pollution and tobacco smoke exposure. METHODS: Information on exposure to SHS and maternal smoking during pregnancy was collected on 3,318 participants at enrollment into the Southern California Children's Health Study. At study entry at average age of 10 years, residential near-roadway pollution exposure (NRP) was estimated based on a line source dispersion model accounting for traffic volume, proximity, and meteorology. Lifetime exposure to tobacco smoke was assessed by parent questionnaire. Associations with subsequent BMI growth trajectory based on annual measurements and attained BMI at 18 years of age were assessed using a multilevel modeling strategy. RESULTS: Maternal smoking during pregnancy was associated with estimated BMI growth over 8-year follow-up (0.72 kg/m2 higher; 95% CI: 0.14, 1.31) and attained BMI (1.14 kg/m2 higher; 95% CI: 0.66, 1.62). SHS exposure before enrollment was positively associated with BMI growth (0.81 kg/m2 higher; 95% CI: 0.36, 1.27) and attained BMI (1.23 kg/m2 higher; 95% CI: 0.86, 1.61). Growth and attained BMI increased with more smokers in the home. Compared with children without a history of SHS and NRP below the median, attained BMI was 0.80 kg/m2 higher (95% CI: 0.27, 1.32) with exposure to high NRP without SHS; 0.85 kg/m2 higher (95% CI: 0.43, 1.28) with low NRP and a history of SHS; and 2.15 kg/m2 higher (95% CI: 1.52, 2.77) with high NRP and a history of SHS (interaction p-value 0.007). These results suggest a synergistic effect. CONCLUSIONS: Our findings strengthen emerging evidence that exposure to tobacco smoke and NRP contribute to development of childhood obesity and suggest that combined exposures may have synergistic effects.

Aurora-C kinase deficiency causes cytokinesis failure in meiosis I and production of large polyploid oocytes in mice.

We previously isolated Aurora-C/Aie1 in a screen for kinases expressed in mouse sperm and eggs. Here, we show the localization of endogenous Aurora-C and examine its roles during female mouse meiosis. Aurora-C was detected at the centromeres and along the chromosome arms in prometaphase I-metaphase I and was concentrated at centromeres at metaphase II, in which Aurora-C also was phosphorylated at Thr171. During the anaphase I-telophase I transition, Aurora-C was dephosphorylated and relocalized to the midzone and midbody. Microinjection of the kinase-deficient Aurora-C (AurC-KD) mRNA into mouse oocytes significantly inhibited Aurora-C activity and caused multiple defects, including chromosome misalignment, abnormal kinetochore-microtubule attachment, premature chromosome segregation, and cytokinesis failure in meiosis I. Furthermore, AurC-KD reduced Aurora-C and histone H3 phosphorylation and inhibited kinetochore localization of Bub1 and BubR1. Similar effects also were observed in the oocytes injected with INCNEP-delIN mRNAs, in which the Aurora-C binding motif was removed. The most dramatic effect observed in AurC-KD-injected oocytes is cytokinesis failure in meiosis I, resulting in producing large polyploid oocytes, a pattern similar to Aurora-C deficiency human spermatozoa. Surprisingly, we detected no Aurora-B protein in mouse oocytes. We propose that Aurora-C, but not Aurora-B, plays essential roles in female mouse meiosis.

Development of novel statistical reconstruction algorithms for poly-energetic X-ray computed tomography.

A beam-hardening effect is a common problem affecting the quantitative aspects of X-ray computed tomography (CT). We have developed two statistical reconstruction algorithms for poly-energetic X-ray CT that can effectively reduce the beam-hardening effect. Phantom tests were used to evaluate our approach in comparison with traditional correction methods. Unlike previous methods, our algorithm utilizes multiple energy-corresponding blank scans to estimate the attenuation map for a particular energy spectrum. Therefore, our algorithm is an energy-selective reconstruction. In addition to benefits over other statistical algorithms for poly-energetic reconstruction, our algorithm has the advantage of not requiring prior knowledge of the object material, the energy spectrum of the source and the energy sensitivity of the detector. The results showed an improvement in coefficient of variation, uniformity and signal-to-noise ratio; overall, this novel approach produces a better beam-hardening correction.

Assessing uncertainty in spatial exposure models for air pollution health effects assessment.

BACKGROUND: Although numerous epidemiologic studies now use models of intraurban exposure, there has been little systematic evaluation of the performance of different models. OBJECTIVES: In this present article we proposed a modeling framework for assessing exposure model performance and the role of spatial autocorrelation in the estimation of health effects. METHODS: We obtained data from an exposure measurement substudy of subjects from the Southern California Children's Health Study. We examined how the addition of spatial correlations to a previously described unified exposure and health outcome modeling framework affects estimates of exposure-response relationships using the substudy data. The methods proposed build upon the previous work, which developed measurement-error techniques to estimate long-term nitrogen dioxide exposure and its effect on lung function in children. In this present article, we further develop these methods by introducing between- and within-community spatial autocorrelation error terms to evaluate effects of air pollution on forced vital capacity. The analytical methods developed are set in a Bayesian framework where multistage models are fitted jointly, properly incorporating parameter estimation uncertainty at all levels of the modeling process. RESULTS: Results suggest that the inclusion of residual spatial error terms improves the prediction of adverse health effects. These findings also demonstrate how residual spatial error may be used as a diagnostic for comparing exposure model performance.

Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection.

BACKGROUND: Evidence from experimental and clinical studies indicates that statins can protect the vessel wall through cholesterol-independent mechanisms. The "pleiotropic" effects include the prevention of inflammation and proliferation of vascular cells. Here, we studied whether heme oxygenase-1 (HO-1), an important cytoprotective molecule, is induced by simvastatin and the role of HO-1 in the pleiotropic effects of simvastatin. METHODS AND RESULTS: Human and rat aortic smooth muscle cells treated with simvastatin showed an elevated level of HO-1 for up to 24 hours. The induction of HO-1 by simvastatin was not found in cultured endothelial cells and macrophages. Injecting C57BL/6J mice intraperitoneally with simvastatin increased the level of HO-1 in vascular SMCs (VSMCs) in the tunica media. Treating VSMCs with zinc protoporphyrin, an HO-1 inhibitor, or HO-1 small interfering RNA (siRNA) blocked the antiinflammatory effect of simvastatin, including the inhibition of nuclear factor-kappaB activation and nitric oxide production. Blockade of HO-1 also abolished the simvastatin-induced p21(Waf1) and the associated antiproliferative effect. Simvastatin activated p38 and Akt in VSMCs, and the respective inhibitors of p38 and phosphoinositide 3-kinase (PI3K) greatly reduced the level of simvastatin-induced HO-1, which suggests the involvement of p38 and the PI3K-Akt pathway in HO-1 induction. CONCLUSIONS: Simvastatin activates HO-1 in VSMCs in vitro and in vivo. The antiinflammatory and antiproliferative effects of simvastatin occur largely through the induced HO-1.

Induction of apoptosis in vascular smooth muscle cells by mechanical stretch.

We studied the response of porcine vascular smooth muscle cells (PVSMCs) to cyclic sinusoidal stretch at a frequency of 1 Hz. Cyclic stretch with an area change of 25% caused an increase in PVSMC apoptosis, which was accompanied by sustained activation of c-Jun NH(2)-terminal kinases (JNK) and the mitogen-activated protein kinase p38. Cyclic stretch with an area change of 7% had no such effect. Infection of PVSMCs with recombinant adenoviruses expressing constitutively active forms of upstream molecules that activate JNK and p38 also led to apoptosis. The simultaneous blockade of both JNK and p38 pathways with adenovirus-mediated expression of dominant-negative mutants of c-Jun and p38 caused a significant decrease (to 1/2) of the apoptosis induced by 25% cyclic stretch. The 25% stretch also caused sustained clustering of tumor necrosis factor-alpha (TNF-alpha) receptor-1 and its association with TNF-alpha receptor-associated factor-2 (TRAF-2). Overexpressing the wild-type TRAF-2 in PVSMCs caused an increase in apoptosis. In contrast, the expression of a dominant-negative mutant of TRAF-2 attenuated stretch-induced apoptois. These results support the hypothesis that circumferential overload under hypertensive conditions induces a clustering of death receptors that cause vascular smooth muscle cell apoptosis.