Terminal differentiation into adipocyte and growth inhibition by PPARγ activation in human A549 lung adenocarcinoma cells.

The present study investigated the terminal differentiation capacity into adipocytes and subsequent growth inhibition in A549 cancer cells treated with pioglitazone (PGZ), a PPARγ activator. The rate of cell growth in A549 cells was significantly (P < .05) inhibited in concentrations above 10 µM PGZ while maintaining less cytotoxic effects in MRC-5 fibroblasts. Following 50 µM PGZ treatment, population doubling time (PDT) was significantly (P < .05) increased by inhibition of cell growth, as per increasing PGZ exposure time by up to 4 weeks. The adiposome-like vesicles were commonly observed in the PGZ-treated A549 cells, and the vesicles were highly stained with Oil-Red O solution. In addition, the cell size and expression of GLUT4 and PPARγ were significantly (P < .05) increased, as per increasing PGZ exposure time by up to 4 weeks. The significant (P < .05) down-regulation of telomerase activity and up-regulation of senescence-associated ß-galactosidase (SA ß-GAL) activity was displayed in the PGZ-treated A549 cells, as per increasing PGZ exposure time by up to 4 weeks. The G1 phase of the cell cycle was also significantly (P < .05) increased in the PGZ-treated A549 cells compared with untreated A549 cells. The present results have demonstrated that activation of PPARγ using PGZ induces cellular differentiation into adipocytes and inhibits cell growth in the A549 cancer cells. The terminal differentiation into adipocytes could offer potent chemotherapy in the cancer cells showing high glucose metabolism.

Inhibition of cell growth by cellular differentiation into adipocyte-like cells in dexamethasone sensitive cancer cell lines.

The stress responses in human body lead to secretion of cortisol hormone. The present study investigated the cellular responses on cell growth and cellular differentiation into adipocytes by exposure of synthetic stress hormone, dexamethasone (DEX) in various human cancer and normal cells. After prolonged exposure of cells with 1 µg/ml DEX for 2 weeks, population doubling time (PDT) was significantly (P < .05) increased by inhibited cell growth in A-549 and MCF-7 cancer cells, and was unchanged in MDA-MB-231 cancer cells, normal MRC-5 fibroblasts, umbilical cord matrix-derived mesenchymal stem cells (UCMSCs) and dental papilla tissue-derived mesenchymal stem cells (DSCs). Whereas, PDT was significantly (P < .05) decreased in U87-MG cancer cells by increased cell growth. Glucose uptake was significantly (P < .05) increased in all the cancer cell lines compared to that in normal cell lines. Further, adiposome-like vesicles were noted in A-549 and MCF-7 cancer cells indicating retarded cell growth by DEX treatment, and the vesicles were stained with Oil-Red O solution. Further, the expression of adipocyte-specific genes such as glucose transporter type 4 (GLUT4), glucocorticoid receptors ß (GRß) and peroxisome proliferator-activated receptor γ (PPARγ) were significantly (P < .05) increased in A-549 and MCF-7 with lipid vesicles. The level of telomerase activity was found to be significantly (P < .05) downregulated in DEX-treated A-549 and MCF-7 cancer cells. Our results have clearly shown that DEX treatment induces inhibition of cell growth by differentiating into adipocyte-like cells in dexamethasone sensitive cancer cells.

Dynamic change in left ventricular apical back rotation: a marker of diastolic suction with exercise.

Aims: We hypothesized that the absence of a decrease in minimal left ventricular (LV) pressure during exercise would be associated with impaired LV apical back rotation during exercise. Methods and results: A total of 21 patients (59 ± 10 years) underwent invasive LV pressure measurements and simultaneous echocardiography at rest and during submaximal supine bicycle exercise. Patients were classified according to the changes in minimal LV pressure from rest to maximal exercise (Δminimal LVP); Group 1 (n = 8) had a decrease in minimal LV pressure with exercise, whereas Group 2 (n = 13) had an increase in minimal LV pressure. LV apical back-rotation parameters by speckle-tracking echocardiography at rest and during 50 W of exercise were compared. At rest, there were no differences in LV pressure and echocardiographic parameters between groups. However, at 50 W of exercise, Group 2 had higher LV early and end-diastolic pressures and a prolonged time constant of LV relaxation. In Group 2, e' velocity was lower and E/e' was higher. Apical back rotation at the mitral valve opening (MVO) was reduced and minimal apical back-rotation velocity was lower in Group 2. Δminimal LVP significantly correlated with apical back rotation at MVO (r = -0.77, P = 0.009) and minimal apical back-rotation velocity at 50 W (r = 0.69, P = 0.028). Conclusion: The lack of decrease in minimal LV pressure during exercise, a manifestation of impaired LV suction in early diastole, is linked closely with impaired LV apical back rotation during exercise. Dynamic changes in LV apical back rotation during exercise can be used as a non-invasive parameter of diastolic suction during exercise.

Deceleration time of left ventricular outflow tract flow as a simple surrogate marker for central haemodynamics at rest and as well as during exercise.

BACKGROUND: The shape and duration of left ventricular outflow tract (LVOT) flow has not been applied to assess the central haemodynamics, although LVOT flow is confronted with afterload of arterial system during systole. The aim of this study was to evaluate whether the LVOT flow parameters are related with central systolic blood pressure (BP) and arterial compliance at rest and as well as during exercise. METHODS: We studied 258 subjects (175 females, age 61 ± 11 years) with normal left ventricular (LV) systolic function who underwent supine bicycle stress echocardiography and arterial tonometry simultaneously at rest and at peak exercise. Deceleration time (DT) of LVOT flow and RR interval were measured and deceleration time corrected for heart rate (DTc) was calculated. Peripheral and central haemodynamic parameters including systolic and diastolic BP, and augmentation index at a heart rate of 75 (AIx@75) were assessed using radial artery tonometry. Carotid femoral pulse wave velocity (PWV) was measured. RESULTRESULTS: Deceleration time corrected for heart rate was independently associated with central systolic BP and AIx@75 at rest (P < 0.001 and 0.006). Similarly, it also showed significant independent correlations with central systolic BP and AIx@75 during peak exercise (P = 0.006 and P = 0.021). In addition, DTc which measured both at rest and at peak exercise demonstrated significant positive correlations with PWV, suggesting association of prolonged DTc with arterial stiffening (P = 0.023 and P = 0.005). CONCLUSION: Prolongation of LVOT flow DTc represents raised central systolic BP and increased arterial stiffness not only at rest but also during exercise. Therefore, central aortic pressures and arterial stiffness influence the DT of LVOT flow at rest as well as during exercise in individuals with normal LV systolic function.

Clinical outcomes of exercise-induced pulmonary hypertension in subjects with preserved left ventricular ejection fraction: implication of an increase in left ventricular filling pressure during exercise.

OBJECTIVE: To investigate clinical outcomes of exercise-induced pulmonary hypertension (PH) and implications of an increase in left ventricular (LV) filling pressure during exercise in subjects with preserved LV ejection fraction. DESIGN: Longitudinal follow-up study. SETTING: Subjects who were referred for diastolic stress echocardiography. PATIENTS AND METHODS: The ratio of transmitral and annular velocities (E/Ea) and pulmonary artery systolic pressure (PASP) at rest and during exercise were measured in 498 subjects (57±11 years; 201 male). Exercise-induced PH was defined as present if PASP ≥50 mm Hg at 50 W of exercise, and an increase in LV filling pressure during exercise was present if E/Ea ≥15 at 50 W. MAIN OUTCOME MEASURES: A combination of major cardiovascular events and any cause of death. RESULTS: During a median follow-up of 41 months, there were 14 hospitalisations and four deaths. Subjects with exercise-induced PH had significantly worse clinical outcomes than those without (p=0.014). Subjects with exercise-induced PH associated with an increase in E/Ea during exercise had significantly worse outcomes than other groups (p<0.001). However, prognosis was similar between subjects with exercise-induced PH without an increase in E/Ea and those without exercise-induced PH. In subjects with exercise-induced PH, E/Ea at 50 W was an independent predictor of adverse outcomes (HR 1.37; 95% CI 1.02 to 1.83; p=0.036). CONCLUSIONS: Exercise-induced PH provides prognostic information in subjects with preserved LV ejection fraction. The excess risk of exercise-induced PH is restricted to subjects with an increase in estimated LV filling pressure during exercise.

Relationship between serum biochemical markers of myocardial fibrosis and diastolic function at rest and with exercise in hypertrophic cardiomyopathy.

BACKGROUND AND OBJECTIVES: Recent studies have demonstrated the usefulness of biochemical markers of collagen turnover as markers of myocardial fibrosis in various diseases. In this study, we hypothesized that increased collagen markers in patients with hypertrophic cardiomyopathy (HCM) were correlated with diastolic function at rest and diastolic functional reserve during exercise. SUBJECTS AND METHODS: Thirty-six patients with HCM and 21 controls with normal left ventricular thickness were studied. Mitral septal annular velocities and mitral inflow velocities were measured at rest and during graded supine bicycle exercise (25 W, 3-minute increments) for the assessment of diastolic function at rest and during exercise. By radioimmunoassay, a byproduct of collagen III synthesis (PIIINP) and peptides resulting from collagen I synthesis (PINP) and degradation (ICTP) were measured. The patients with HCM were divided into two groups according to the median value of the PINP/ICTP ratio in the group. RESULTS: At rest, the mitral annular early diastolic velocity (E') was lower and the E/E' was higher in the patients with HCM with high a PINP/ICTP ratio compared with patients with HCM with a low PINP/ICTP ratio and controls (p<0.001, p=0.012). With exercise, the Doppler parameters were increased in all groups, but there was no significant difference in the change in E' and E/E' during exercise according to collagen turnover markers. CONCLUSION: A higher PINP/ICTP ratio was associated with resting diastolic dysfunction in patients with HCM; however, there was no relationship with augmented diastolic dysfunction during exercise. We suggest that the type I collagen synthesis-to-degradation ratio is a useful marker of resting diastolic function in patients with HCM.