Overview of knowledge, attitudes and barriers associated with HPV vaccination in Beirut, Lebanon.

BACKGROUND: Human Papillomavirus (HPV), a prevalent sexually transmitted infection carrying significant risks ranging from benign lesions to various types of malignancies, represents a matter of great public health concern. Notably, most Arab countries lack public awareness campaigns or national immunization programs. This study aims at assessing the overall knowledge on HPV and HPV vaccination among the Lebanese population, exploring the prevalent attitude on the matter, and identifying barriers and misconceptions that prevent individuals from receiving the HPV vaccine. METHODS: A cross-sectional study was conducted in Beirut, on 201 participants aged between 18 and 36 years old. We performed ordinal analysis to assess the trend between Knowledge levels, attitude levels and hesitancy Levels. RESULTS: Majority of participants (77%) demonstrated a low level of knowledge on HPV vaccination, 50% held a positive attitude, with only 18.4% being already vaccinated. Negative trend was identified between levels of knowledge, attitude and hesitancy (gamma = -0.7415, p-value < 0.01; gamma= -0.58, p-value < 0.01 respectively). Unavailability or limited access to the vaccine, and misconceptions about HPV immunization were shown to be impeding vaccination. CONCLUSION: Analysis of our results strongly suggests that improving knowledge and attitudes is likely to foster trust and reduce hesitancy, thereby promoting higher vaccine uptake.

Diabetes and the social, biologic, and behavioral determinants of endometrial cancer in the United States.

BACKGROUND: Endometrial cancer is one of the most common types of cancer that affects women's reproductive system. The risk of endometrial cancer is associated with biologic, behavioral and social determinants of health (SDOH). The focus of the work is to investigate the cumulative effect of this cluster of covariates on the odds of endometrial cancer that heretofore have only been considered individually. METHODS: We conducted a quantitative study using the Behavioral Risk Factor Surveillance System (BRFSS) national data collected in 2020. Data analysis using weighted Chi-square test and weighted logistic regression were carried out on 84,118 female study participants from the United States. RESULTS: Women with diabetes mellitus were approximately twice as likely to have endometrial cancer compared to women without diabetes (OR 1.54; 95%CI: 1.01-2.34). Biologic factors that included obesity (OR 3.10; 95% CI: 1.96-4.90) and older age (with ORs ranging from 2.75 to 7.21) had a significant increase in the odds of endometrial cancer compared to women of normal weight and younger age group of 18 to 44. Among the SDOH, attending college (OR 1.83; 95% CI: 1.12-3.00) was associated with increased odds of endometrial cancer, while renting a home (OR 0.50; 95% CI: 0.28-0.88), having other arrangements (OR 0.05; 95% CI: 0.02-0.16), being divorced (OR 0.55; 95% CI: 0.30-0.99), and having higher incomes ranging from $35,000 to $50,000 (OR 0.35; 95% CI: 0.16-0.78), and above $50,000 (OR 0.29; 95% CI: 0.14-0.62), were all associated with decreased odds of endometrial cancer. As for race, Black women (OR 0.24; 95% CI: 0.07-0.84) and women of other races (OR 0.37; 95% CI: 0.15-0.88) were shown to have lower odds of endometrial cancer compared to White women. CONCLUSION: Our results revealed the importance of adopting a comprehensive approach to the study of the associated factors of endometrial cancer by including social, biologic, and behavioral determinants of health. The observed social inequity in endometrial cancer among women needs to be addressed through effective policies and changes in social structures to advocate for a standardized healthcare system that ensures equitable access to preventive measures and quality of care.

Role of Insulin Use and Social Determinants of Health on Non-melanoma Skin Cancer: Results From the Behavioral Risk Factor Surveillance System.

BACKGROUND: Non-melanoma skin cancer (NMSC) is a frequent type of malignancy with a steadily increasing incidence rate worldwide. Although NMSC was shown to be associated with diabetes, no studies have addressed the extent to which insulin use influences the risk of NMSC in light of social determinants of health (SDOH). We conducted a quantitative study that examined the interplay between insulin use, SDOH, additional covariates, and NMSC among individuals with diabetes. METHODS: We based our analysis on the 2020 Behavioral Risk Factor Surveillance System (BRFSS), a national survey conducted yearly in the US. We performed weighted chi-squared test, logistic regression, and survival analyses on 8685 eligible participants with diabetes enrolled in the BRFSS. RESULTS: Kaplan Meier survival curves showed higher probability of NMSC event-free survival for participants with diabetes using insulin compared to participants with diabetes not using insulin (log-rank test P < .001). Significant associations were detected between insulin use and reduced odds of NMSC (OR .56; 95% CI: .38-.82), and decreased hazard (HR .36; 95% CI: .21-.62), along with indices of SDOH. CONCLUSIONS: Our findings suggest that socioeconomic differences related to the healthcare system and behavioral patterns are linked to discrepancies in the use of insulin and the development of NMSC.

Social and racial inequalities in diabetes and cancer in the United States.

Background: Cancer and diabetes are among the leading causes of morbidity and mortality worldwide. Several studies have reported diabetes as a risk factor for developing cancer, a relationship that may be explained by associated factors shared with both diseases such as age, sex, body weight, smoking, and alcohol consumption. Social factors referred to as social determinants of health (SDOH) were shown to be associated with the risk of developing cancer and diabetes. Despite that diabetes and social factors were identified as significant determinants of cancer, no studies examined their combined effect on the risk of developing cancer. In this study, we aim at filling this gap in the literature by triangulating the association between diabetes, indices of SDOH, and the risk of developing cancer. Methods: We have conducted a quantitative study using data from the Behavioral Risk Factor Surveillance System (BRFSS), whereby information was collected nationally from residents in the United States (US) with respect to their health-related risk behaviors, chronic health conditions, and the use of preventive services. Data analysis using weighted regressions was conducted on 389,158 study participants. Results: Our findings indicated that diabetes is a risk factor that increases the likelihood of cancer by 13% (OR 1.13; 95%CI: 1.05-1.21). People of White race had higher odds for cancer compared to African Americans (OR 0.44; 95%CI: 0.39-0.49), Asians (OR 0.27; 95%CI: 0.20-0.38), and other races (OR 0.56; 95%CI: 0.46-0.69). The indices of SDOH that were positively associated with having cancer encompassed unemployment (OR 1.78; 95%CI: 1.59-1.99), retirement (OR 1.54; 95%CI: 1.43-1.67), higher income levels with ORs ranging between 1.16-1.38, college education (OR 1.10; 95%CI: 1.02-1.18), college graduates (OR 1.31; 95%CI: 1.21-1.40), and healthcare coverage (OR 1.44; 95%CI: 1.22-1.71). On the other hand, the indices of SDOH that were protective against having cancer were comprised of renting a home (OR 0.86; 95%CI: 0.79-0.93) and never married (OR 0.73; 95%CI: 0.65-0.81). Conclusion: This study offers a novel social dimension for the association between diabetes and cancer that could guide setting strategies for addressing social inequities in disease prevention and access to healthcare.

General Versus Locoregional Anesthesia in TEVAR: An NSQIP Analysis.

BACKGROUND: Thoracic Endovascular Aortic Repair (TEVAR) is a minimally invasive surgery for repairing thoracic aneurysms and dissections. This study aims to compare postoperative outcomes of TEVAR performed under general versus locoregional anesthesia. METHODS: Utilizing the 2008-2019 American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database, patients older than the age of 18 years who received TEVAR, were identified using the following current procedural terminology codes: 33,880, 33,881, 33,883, 33,884, or 33,886. Patients who underwent concomitant procedures, those with both thoracoabdominal and abdominal aortic pathologies, and trauma cases were excluded. Standard descriptive statistics, in addition to χ2, Fisher's exact test, and Mann-Whitney U-tests were used to compare patient baseline characteristics and postoperative outcomes between general and locoregional anesthesia groups as appropriate. Univariable and multivariable logistic regression analyses were performed to assess independent predictors of hospital length of stay (LOS) greater than 7 days. RESULTS: Of the 1,028 patients included in the study, 86.5% received general anesthesia, and 13.5% received locoregional anesthesia, such as local anesthesia with monitored anesthesia care or regional anesthesia. No significant differences were found between patients receiving locoregional versus general anesthesia in mortality (3.6% vs. 7.9%, respectively, P = 0.071) and morbidity (18.7% and 24.8%, respectively, P = 0.121) within 30 days post-TEVAR, including any wound, pulmonary, thromboembolic, renal, septic, and cardiac arrest complications. Patients who received general anesthesia had significantly higher median LOS compared to those who received locoregional anesthesia [5 days (interquartile range (IQR): 3-10) versus 4 days (IQR: 2-7), P = 0.002], with 34.3% of the general anesthesia group having an LOS greater than 7 days compared to 21.6% of locoregional anesthesia group, P = 0.003. On multivariable logistic regression analysis, general anesthesia was found to be an independent predictor of prolonged LOS greater than 7 days (odds ratio (OR): 1.72, 95% confidence interval (CI): 1.05-2.81, P = 0.031). CONCLUSIONS: Locoregional anesthesia results in significantly lower postoperative hospital LOS with similar postoperative mortality and morbidity compared to general anesthesia in patients undergoing TEVAR.

Exercise-Induced Ventricular Ectopy and Cardiovascular Mortality in Asymptomatic Individuals.

BACKGROUND: The prognosis of exercise-induced premature ventricular contractions (PVCs) in asymptomatic individuals is unclear. OBJECTIVES: This study sought to investigate whether high-grade PVCs during stress testing predict mortality in asymptomatic individuals. METHODS: A cohort of 5,486 asymptomatic individuals who took part in the Lipid Research Clinics prospective cohort had baseline interview, physical examination, blood tests, and underwent Bruce protocol treadmill testing. Adjusted Cox survival models evaluated the association of exercise-induced high-grade PVCs (defined as either frequent (>10 per minute), multifocal, R-on-T type, or ≥2 PVCs in a row) with all-cause and cardiovascular mortality. RESULTS: Mean baseline age was 45.4 ± 10.8 years; 42% were women. During a mean follow-up of 20.2 ± 3.9 years, 840 deaths occurred, including 311 cardiovascular deaths. High-grade PVCs occurred during exercise in 1.8% of individuals, during recovery in 2.4%, and during both in 0.8%. After adjusting for age, sex, diabetes, hypertension, lipids, smoking, body mass index, and family history of premature coronary disease, high-grade PVCs during recovery were associated with cardiovascular mortality (hazard ratio [HR]: 1.82; 95% CI: 1.19-2.79; P = 0.006), which remained significant after further adjusting for exercise duration, heart rate recovery, achieving target heart rate, and ST-segment depression (HR: 1.68; 95% CI: 1.09-2.60; P = 0.020). Results were similar by clinical subgroups. High-grade PVCs occurring during the exercise phase were not associated with increased risk. Recovery PVCs did not improve 20-year cardiovascular mortality risk discrimination beyond clinical variables. CONCLUSIONS: High-grade PVCs occurring during recovery were associated with long-term risk of cardiovascular mortality in asymptomatic individuals, whereas PVCs occurring only during exercise were not associated with increased risk.

The association of cardiovascular mortality with a first-degree family member history of different cardiovascular diseases.

OBJECTIVE: To investigate which history of cardiovascular disease [coronary heart disease (CHD), stroke, or peripheral arterial disease] in a first-degree family member predicts cardiovascular mortality. METHODS: We studied a prospective cohort (the Lipid Research Clinics Prevalence Study) from ten primary care centers across North America. The primary outcome was cardiovascular mortality, assessed using Cox survival models. RESULTS: There were 8,646 participants (mean age: 47.4 ± 12.1 years, 46% women, 52% of participants with hyperlipidemia) who were followed up for a mean duration of 19.4 ± 4.9 years. There were 1,851 deaths (21%), including 852 cardiovascular deaths. A paternal, maternal or sibling history of premature CHD (before 60 years) was present in 26% of participants, of stroke in 27% of participants, and of peripheral arterial disease in 24% of participants. After adjusting for risk factors (age, sex, systolic blood pressure, diastolic blood pressure, body mass index, smoking, fasting glucose, low-density lipoprotein cholesterol and triglycerides), only a paternal history of premature or any CHD, a maternal history of diabetes mellitus or premature or any CHD, and a sibling history of premature CHD, hypertension, or hyperlipidemia were individually predictive of cardiovascular mortality. After adjusting for risk factors and the mentioned familial factors, only paternal and maternal histories of CHD, especially before 60 years, remained predictive of cardiovascular mortality, with a somewhat higher association for a maternal history [adjusted hazard ratio (aHR) = 1.99, 95% CI: 1.36-2.92,P < 0.001 for maternal history of premature CHD; aHR = 1.52, 95% CI: 1.10-2.10, P = 0.011 for paternal history of premature CHD]. Family history of stroke or peripheral arterial disease did not predict cardiovascular mortality. Parental history of premature CHD predicted cardiovascular mortality independently of baseline age (< 60 years and ≥ 60 years), hypertension, or hyperlipidemia and carried more important prognostic value in men rather than women. CONCLUSIONS: In this study, a parental history of CHD, especially before 60 years, best predicted cardiovascular mortality. This finding could help more accurately identify high-risk patients who would benefit from preventive strategies.

Plasma Kallikrein as a Modulator of Liver Injury/Remodeling.

The occurrence and persistence of hepatic injury which arises from cell death and inflammation result in liver disease. The processes that lead to liver injury progression and resolution are still not fully delineated. The plasma kallikrein-kinin system (PKKS) has been shown to play diverse functions in coagulation, tissue injury, and inflammation, but its role in liver injury has not been defined yet. In this study, we have characterized the role of the PKKS at various stages of liver injury in mice, as well as the direct effects of plasma kallikrein on human hepatocellular carcinoma cell line (HepG2). Histological, immunohistochemical, and gene expression analyses were utilized to assess cell injury on inflammatory and fibrotic factors. Acute liver injury triggered by carbon tetrachloride (CCl4) injection resulted in significant upregulation of the plasma kallikrein gene (Klkb1) and was highly associated with the high mobility group box 1 gene, the marker of cell death (r = 0.75, p < 0.0005, n = 7). In addition, increased protein expression of plasma kallikrein was observed as clusters around necrotic areas. Plasma kallikrein treatment significantly increased the proliferation of CCl4-induced HepG2 cells and induced a significant increase in the gene expression of the thrombin receptor (protease activated receptor-1), interleukin 1 beta, and lectin-galactose binding soluble 3 (galectin-3) (p < 0.05, n = 4). Temporal variations in the stages of liver fibrosis were associated with an increase in the mRNA levels of bradykinin receptors: beta 1 and 2 genes (p < 0.05; n = 3-10). In conclusion, these findings indicate that plasma kallikrein may play diverse roles in liver injury, inflammation, and fibrosis, and suggest that plasma kallikrein may be a target for intervention in the states of liver injury.

Vascular Cells Proteome Associated with Bradykinin and Leptin Inflammation and Oxidative Stress Signals.

Among the primary contributors to cardiovascular diseases are inflammation and oxidative imbalance within the vessel walls as well as the fibrosis of rat aortic smooth muscle cell (RASMC). Bradykinin (BK) and leptin are inflammatory modulators that are linked to vascular injury. In this study, we employed tandem LC-MS/MS to identify protein signatures that encompass protein abundance in RASMC treated with BK or leptin followed by systems biology analyses to gain insight into the biological pathways and processes linked to vascular remodeling. In the study, 1837 proteins were identified in control untreated RASMC. BK altered the expression of 72 (4%) and 120 (6.5%) proteins, whereas leptin altered the expression of 189 (10.2%) and 127 (6.5%) proteins after 24 and 48 h, respectively, compared to control RASMC. BK increased the protein abundance of leptin receptor, transforming growth factor-ß. On the other hand, leptin increased the protein abundance of plasminogen activator inhibitor 1 but decreased the protein abundance of cofilin. BK and leptin induced the expression of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-1ß (IL-1ß) and pathway analysis revealed the activation of mitogen-activated protein kinases (MAPKs) and AKT pathways. The proteome profile in response to BK and leptin revealed mechanistic interplay of multiple processes that modulate inflammation and oxidative stress signals in the vasculature.

Thymoquinone induces apoptosis and DNA damage in 5-Fluorouracil-resistant colorectal cancer stem/progenitor cells.

The high recurrence rates of colorectal cancer have been associated with a small population of cancer stem cells (CSCs) that are resistant to the standard chemotherapeutic drug, 5-fluorouracil (5FU). Thymoquinone (TQ) has shown promising antitumor properties on numerous cancer systems both in vitro and in vivo; however, its effect on colorectal CSCs is poorly established. Here, we investigated TQ's potential to target CSCs in a three-dimensional (3D) sphere-formation assay enriched for a population of colorectal cancer stem/progenitor cells. Our results showed a significant decrease in self-renewal potential of CSC populations enriched from 5FU-sensitive and resistant HCT116 cells at 10-fold lower concentrations when compared to 2D monolayers. TQ decreased the expression levels of colorectal stem cell markers CD44 and Epithelial Cell Adhesion Molecule EpCAM and proliferation marker Ki67 in colonospheres derived from both cell lines and reduced cellular migration and invasion. Further investigation revealed that TQ treatment led to increased TUNEL positivity and a dramatic increase in the amount of the DNA damage marker gamma H2AX particularly in 5FU-resistant colonospheres, suggesting that the diminished sphere forming ability in TQ-treated colonospheres is due to induction of DNA damage and apoptotic cell death. The intraperitoneal injection of TQ in mice inhibited tumor growth of spheres derived from 5FU-sensitive and 5FU-resistant HCT116 cells. Furthermore, TQ induced apoptosis and inhibited NF-κB and MEK signaling in mouse tumors. Altogether, our findings document TQ's effect on colorectal cancer stem-like cells and provide insights into its underlying mechanism of action.

Knowledge and attitudes towards E-cigarette use in Lebanon and their associated factors.

BACKGROUND: Despite the misconceptions regarding E-cigarettes (ECs), only a few studies have been conducted in the Middle East that focused on this topic. This study assesses the knowledge of and attitudes towards ECs in Lebanon, determines how these two measures are associated, and identifies the variables that explain each of these measures. METHODS: A cross sectional study was conducted on a convenience sample of Lebanese pedestrians aged between 18 and 64 inclusive. A structured self-administered questionnaire comprising of knowledge and attitude scales, and questions on demographical, health and smoking characteristics was used. RESULTS: Scores for attitudes and knowledge of ECs were summed and dichotomized using a 75% cutoff, above which the participant was considered to have a positive attitude and good knowledge. Among the 352 participants (56.6% males, 43.3% females, mean age 30.3, 46.2% smokers), 63.3% exhibited a lower level of EC knowledge. More than 50% erroneously thought that ECs are not associated with lung and bladder cancer or impair lung and heart function. 65% falsely thought that it is harmless and not addictive. As for attitude, 43.3, 53.9, and 44.3% thought that it is socially acceptable, helps in smoking cessation, and is a good replacement for cigarettes and an enjoyable recreational device respectively. Our results revealed an inverse correlation between attitude and knowledge scores (Spearman's correlation = -.30, p < .001). Predictors of knowledge included health-related occupation (p = .010), regular exercise (p = .016), healthy diet (p = .026), EC use (p = .026), perception that ECs are not harmful (p = .001), and help in smoking cessation (p = .017). Predictors of attitude included EC use (p = .008), sex (p = .010), and knowledge that most ECs are addictive (p = .006), harmful (p = .014), and impair heart and lung function (p = .047). CONCLUSIONS: Our study revealed a gap in EC knowledge, especially among participants who displayed a positive attitude towards ECs. Hence, measures should be undertaken to regulate its use by instituting more stringent laws and holding nationwide awareness campaigns.

Awareness of Colorectal Cancer and Attitudes Towards Its Screening Guidelines in Lebanon.

BACKGROUND: Screening for colorectal cancer (CRC) provides an effective strategy for early detection and prevention of the disease; however, global screening rates are still low. PURPOSE: This study aims at assessing the awareness of CRC risk factors, warning signs, and attitudes towards CRC guidelines and screening modalities, in order to identify the barriers to and correlates of CRC screening in the Lebanese population. METHODS: A self-administered questionnaire was distributed to 371 participants in the largest health care medical center in Lebanon. A validated 12- and 9-item Cancer Awareness Measurement questionnaire was used to assess participants' awareness of CRC risk factors and warning signs. RESULTS: 83% and 67% of participants were not aware of CRC risk factors and warning signs, respectively, 15% have previously undergone CRC screening, 56% were aware of the necessity for screening, and 43% were willing to undergo screening. Factors affecting awareness of the necessity for CRC screening, past screening and willingness to screen included awareness of risk factors and warning signs, undergoing regular physician check-ups, having a family physician as a primary source of knowledge of CRC, and knowing a family member or friend diagnosed with CRC. Barriers to screening were related to participants' evaluation of the screening technique and misconceptions about this disease. CONCLUSION: Serious active measures should be taken by health care sectors, authoritative groups, primary care physicians, and awareness campaigns to fill the gap in awareness of this disease and to alleviate the barriers and misconceptions around it.

Analysis of longitudinal semicontinuous data using marginalized two-part model.

BACKGROUND: Connective tissue growth factor (CTGF), is a secreted matricellular factor that has been linked to increased risk of cardiovascular disease in diabetic subjects. Despite the biological role of CTGF in diabetes, it still remains unclear how CTGF expression is regulated. In this study, we aim to identify the clinical parameters that modulate plasma CTGF levels measured longitudinally in type 1 diabetic patients over a period of 10 years. A number of patients had negligible measured values of plasma CTGF that formed a point mass at zero, whereas others had high positive values of CTGF that were measured on a continuous scale. The observed combination of excessive zero and continuous positively distributed non-zero values in the CTGF outcome is referred to as semicontinuous data. METHODS: We propose a novel application of a marginalized two-part model (mTP) extended to accommodate longitudinal semicontinuous data in which the marginal mean is expressed in terms of the covariates and estimates of their effect on the mean responses are generated. The continuous component is assumed to follow distributions that stem from the generalized gamma family whereas the binary measure is analyzed using logistic model and both have correlated random effects. Other approaches including the one- and two-part with uncorrelated and correlated random effects models were also applied and their estimates were all compared. RESULTS: Our results using the mTP model identified intensive glucose control treatment and smoking as clinical factors that were associated with decreased and increased odds of observing non-zero CTGF values respectively. In addition, hemoglobin A1c, systolic blood pressure, and high density lipoprotein were all shown to be significant risk factors that contribute to increasing CTGF levels. These findings were consistently observed under the mTP model but varied with the distributions for the other models. Accuracy and precision of the mTP model was further validated using simulation studies. CONCLUSION: The mTP model identified new clinical determinants that modulate the levels of CTGF in diabetic subjects. Applicability of this approach can be extended to other biomarkers measured in patient populations that display a combination of negligible zero and non-zero values.

Proteome profiling in the aorta and kidney of type 1 diabetic rats.

Diabetes is associated with a number of metabolic and cardiovascular risk factors that contribute to a high rate of microvascular and macrovascular complications. The risk factors and mechanisms that contribute to the development of micro- and macrovascular disease in diabetes are not fully explained. In this study, we employed mass spectrometric analysis using tandem LC-MS/MS to generate a proteomic profile of protein abundance and post-translational modifications (PTM) in the aorta and kidney of diabetic rats. In addition, systems biology analyses were employed to identify key protein markers that can provide insights into molecular pathways and processes that are differentially regulated in the aorta and kidney of type 1 diabetic rats. Our results indicated that 188 (111 downregulated and 77 upregulated) proteins were significantly identified in the aorta of diabetic rats compared to normal controls. A total of 223 (109 downregulated and 114 upregulated) proteins were significantly identified in the kidney of diabetic rats compared to normal controls. When the protein profiles from the kidney and aorta of diabetic and control rats were analyzed by principal component analysis, a distinct separation of the groups was observed. In addition, diabetes resulted in a significant increase in PTM (oxidation, phosphorylation, and acetylation) of proteins in the kidney and aorta and this effect was partially reversed by insulin treatment. Ingenuity pathway analysis performed on the list of differentially expressed proteins depicted mitochondrial dysfunction, oxidative phosphorylation and acute phase response signaling to be among the altered canonical pathways by diabetes in both tissues. The findings of the present study provide a global proteomics view of markers that highlight the mechanisms and putative processes that modulate renal and vascular injury in diabetes.

Evidence for prostacyclin and cAMP upregulation by bradykinin and insulin-like growth factor 1 in vascular smooth muscle cells.

Although bradykinin (BK) and insulin like growth factor-1 (IGF-1) have been shown to modulate the functional and structural integrity of the arterial wall, the cellular mechanisms through which this regulation occurs is still undefined. The present study examined the role of second messenger molecules generated by BK and IGF-1 that could ultimately result in proliferative or antiproliferative signals in vascular smooth muscle cells (VSMC). Activation of BK or IGF-1 receptors stimulated the synthesis and release of prostacyclin (PGI(2)) leading to increased production of cAMP in VSMC. Inhibition of p42/p44(mapk) or src kinases prevented the increase in PGI(2) and cAMP observed in response to BK or IGF-1, indicating a role for these kinases in the regulation of cPLA(2) activity in the VSMC. Inhibition of PKC failed to alter production of PGI(2) in response to BK, but further increased both p42/p44(mapk) activation and the synthesis of PGI(2) produced in response to IGF-1. In addition, both BK and IGF-1 significantly induced the expression of c-fos mRNA levels in VSMC, and this effect of BK was accentuated in the presence a cPLA(2) inhibitor. Finally, inhibition of cPLA(2) activity and/or cyclooxygenase activity enhanced the expression of collagen I mRNA levels in response to BK and IGF-1 stimulation. These findings indicate that the effect of BK or IGF-1 to stimulate VSMC growth is an integrated response to the activation of multiple signaling pathways. Thus, the excessive cell growth that occurs in certain forms of vascular disease could reflect dysfunction in one or more of these pathways.