The dopamine D1 receptor is expressed and induces CREB phosphorylation and MUC5AC expression in human airway epithelium

Background Dopamine receptors comprise two subgroups, Gs protein-coupled “D1-like” receptors (D1, D5) and Gi-coupled “D2-like” receptors (D2, D3, D4). In airways, both dopamine D1 and D2 receptors are expressed on airway smooth muscle and regulate airway smooth muscle force. However, functional expression of the dopamine D1 receptor has never been identified on airway epithelium. Activation of Gs-coupled receptors stimulate adenylyl cyclase leading to cyclic AMP (cAMP) production, which is known to induce mucus overproduction through the cAMP response element binding protein (CREB) in airway epithelial cells. We questioned whether the dopamine D1 receptor is expressed on airway epithelium, and whether it promotes CREB phosphorylation and MUC5AC expression. Methods We evaluated the protein expression of the dopamine D1 receptor on native human airway epithelium and three sources of cultured human airway epithelial cells including primary cultured airway epithelial cells, the bronchial epithelial cell line (16HBE14o-), and the pulmonary mucoepidermoid carcinoma cell line (NCI-H292) using immunohistochemistry and immunoblotting. To characterize the stimulation of cAMP through the dopamine D1 receptor, 16HBE14o- cells and NCI-H292 cells were treated with dopamine or the dopamine D1 receptor agonists (SKF38393 or A68930) before cAMP measurements. The phosphorylation of CREB by A68930 in both 16HBE14o- and NCI-H292 cells was measured by immunoblot. The effect of dopamine or A68930 on the expression of MUC5AC mRNA and protein in NCI-H292 cells was evaluated by real-time PCR and immunofluorescence staining, respectively. Results The dopamine D1 receptor protein was detected in native human airway epithelium and three sources of cultured human airway epithelial cells. Dopamine or the dopamine D1-like receptor agonists stimulated cAMP production in 16HBE14o- cells and NCI-H292 cells, which was reversed by the selective dopamine D1-like receptor antagonists (SCH23390 or SCH39166). A68930 significantly increased phosphorylation of CREB in both 16HBE14o- and NCI-H292 cells, which was attenuated by the inhibitors of PKA (H89) and MEK (U0126). Expression of MUC5AC mRNA and protein were also increased by either dopamine or A68930 in NCI-H292 cells. Conclusions These results suggest that the activation of the dopamine D1 receptor on human airway epithelium could induce mucus overproduction, which could worsen airway obstructive symptoms

Risk factors and in-hospital outcomes in stroke and myocardial infarction patients

BACKGROUND: Acute stroke (AS) and acute myocardial infarction (AMI) share major risk factors such as age, gender, and high blood pressure. The main objective of this study was to compare vascular risk factor profiles with in-hospital outcomes in AS and AMI patients. METHODS: We evaluated 486 consecutive patients who were admitted to Bjelovar General Hospital with diagnoses of AS (ischaemic stroke or intracerebral haemorrhage; N = 380) or AMI (N = 106) during a one year period. The frequency of risk factors and in-patient mortality rates were assessed in both groups. For statistical analysis we used t-tests and χ(2 )tests. RESULTS: AS patients were significantly older than AMI patients: the mean age for AS patients was 68.9 ± 9.1 years, and for AMI patients was 62.8 ± 11.7 years (p < 0.001). AMI was significantly more common than AS in patients younger than 65 years; 51% of this group had AMI and 26% had AS (p < 0.001). Hypertension was a more common risk factor in AS patients (69% AS patients vs. 58% AMI patients; p = 0.042). Patients who died did not differ significantly in age between the groups. In-patient mortality rates were significantly higher in AS than AMI cases (31% vs. 12%, p < 0.001 for all patients; 37% vs.5%, p < 0.001 for men). Women hospitalized for AMI were more likely to die in hospital than men (28% vs. 5%; p = 0.002). CONCLUSIONS: We found that age at the time of presentation was a significant differentiating factor between patients with AS and AMI. The only exceptions were women, whose ages at the onset of AS and AMI were similar. In contrast, patients who died did not differ significantly in age. We observed significantly higher inpatient mortality for men (when adjusted for age) than for women with AS. The five-fold higher in-patient mortality rate in women than in men with AMI is most likely to have resulted from other factors related to treatment

Stroke in women — from evidence to inequalities

Stroke is the second largest cause of disability-adjusted life-years lost worldwide. The prevalence of stroke in women is predicted to rise rapidly, owing to the increasing average age of the global female population. Vascular risk factors differ between women and men in terms of prevalence, and evidence increasingly supports the clinical importance of sex differences in stroke. The influence of some risk factors for stroke — including diabetes mellitus and atrial fibrillation — are stronger in women, and hypertensive disorders of pregnancy also affect the risk of stroke decades after pregnancy. However, in an era of evidence-based medicine, women are notably under-represented in clinical trials — despite governmental actions highlighting the need to include both men and women in clinical trials — resulting in a reduced generalizability of study results to women. The aim of this Review is to highlight new insights into specificities of stroke in women, to plan future research priorities, and to influence public health policies to decrease the worldwide burden of stroke in women