BackgroundWe have previously shown that the thromboxane (TXA2) receptor agonist, U46619, can directly induce ventricular arrhythmias that were associated with increases in intracellular calcium in cardiomyocytes. Since TXA2 is an inflammatory mediator and induces direct calcium changes in cardiomyocytes, we hypothesized that TXA2 released during ischemia or inflammation could also cause cardiac remodeling.MethodsU46619 (0.1-10 μM) was applied to isolated adult mouse ventricular primary cardiomyocytes, mouse ventricular cardiac muscle strips, and cultured HL-1 cardiomyocytes and markers of hypertrophy and cell death were measured.ResultsWe found that TXA2 receptors were expressed in ventricular cardiomyocytes and were functional via calcium imaging. U46619 treatment for 24 h did not increase expression of pathological hypertrophy genes (atrial natriuretic peptide, β-myosin heavy chain, skeletal muscle α-actin) and it did not increase protein synthesis. There was also no increase in cardiomyocyte size after 48 h treatment with U46619 as measured by flow cytometry. However, U46619 (0.1-10 μM) caused a concentration-dependent increase in cardiomyocyte death (trypan blue, MTT assays, visual cell counts and TUNEL stain) after 24 h. Treatment of cells with the TXA2 receptor antagonist SQ29548 and inhibitors of the IP3 pathway, gentamicin and 2-APB, eliminated the increase in cell death induced by U46619.ConclusionsOur data suggests that TXA2 does not induce cardiac hypertrophy, but does induce cell death that is mediated in part by IP3 signaling pathways. These findings may provide important therapeutic targets for inflammatory-induced cardiac apoptosis that can lead to heart failure.
Background: Smoking is a common habit prevalent in both urban and rural areas of India. Cigarette smoking has extensive effects on respiratory function and is clearly implicated in the etiology of a number of respiratory diseases, particularly chronic bronchitis, emphysema, and bronchial carcinoma. An attempt has been made to study the pulmonary function tests among the smoking and non-smoking population in the urban area of Secunderabad, Telangana, South India. Objective: The primary objective of this research was to study the influence of smoking on pulmonary functions. Design: This was a cross-sectional study. Duration: One year i.e. from November 2014 to October 2015. Setting: Gandhi Hospital, Secunderabad, Telangana, South India. Participants: 80 patients attending the Medicine Out Patient Department, Gandhi Hospital. Methods: The study subjects were classified as smokers or non-smokers based on WHO suggested classification criteria. After recording detailed history, smoking index was calculated for smokers to evaluate dose-duration response relationship. Spirometry was performed to assess the pulmonary function of the subjects. The results are given as Mean ± Standard deviation and Standard error values. Comparison performed using student’s t-test for 2 groups. The P value of 0.05 or less was considered significant. Results: 57.5% of smokers were light smokers, 27.5% were moderate and 15% heavy smokers. FVC was significantly lower in smokers compared with non-smokers(p<0.05), Also this decrease was significantly higher as the no. of cigarettes smoked per day increased(p<0.05). FEF25-75% was also found to be significantly reduced in smokers compared with non-smokers. PEFR was significantly reduced in smokers and even this parameter showed a comparable fall(p<0.05) with intensity and duration of smoking. FEV1 also showed a significant decrease in smokers especially those with greater duration and amount of smoking (p<0.05). FEV1/FVC ratio showed a significant fall in smokers compared with non-smokers(p<0.05), but this fall was not so significant as the no. of cigarettes smoked per day increased(p>0.05), however like other indices FEV1/FVC showed a significant decrease(p<0.05) as the duration of smoking increased. Conclusion: It may be concluded that smoking causes definite pulmonary function impairments, especially the obstructive type. Keywords: Lung Volumes, Lung Capacities, Comparision, Smokers, Non-Smokers.
We have shown that the inflammatory mediator thromboxane A2 (TxA2) can induce ventricular arrhythmias that were associated with increased intracellular calcium in cardiomyocytes. We were able to prevent both the arrhythmias and the changes in intracellular calcium by inhibiting inositol trisphosphate (IP3) signaling. In this investigation, we sought to determine if TxA2 receptor (TxA2R) activation would trigger apoptosis in isolated adult mouse cardiomyocytes. Our hypothesis is that TxA2R‐stimulation induces IP3 formation and subsequent IP3 receptor activation triggers apoptosis. We found that TxA2Rs were expressed in the ventricles and that there was a concentration dependent increase in cell death (Trypan blue and MTT assays) following treatment with the TxA2 mimetic U46619 (0.1–10 μM). We have confirmed that TxA2‐induced death was apoptotic via cleaved caspase‐3 and TUNEL staining. Treatment of cells with the TxA2R antagonist SQ29548 and the IP3 inhibitors Gentamycin and 2‐APB eliminated the increase in apoptosis by U46619. In conclusion, our data suggests that: 1) TxA2‐induced cell death is mediated in part by apoptosis and 2) the IP3 pathway is a novel mediator of apoptosis in cardiomyocytes. These findings may provide important therapeutic targets for inflammatory‐induced cardiac apoptosis that can lead to heart failure. (AHA 11SDG5330016 to MJW)
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