Function of Mitochondrial Stat3 in Cellular Respiration Wegrzyn, Joanna; Potla, Ramesh; Chwae, Yong-Joon ...
Science (American Association for the Advancement of Science),
02/2009, Volume:
323, Issue:
5915
Journal Article
Peer reviewed
Open access
Cytokines such as interleukin-6 induce tyrosine and serine phosphorylation of Stat3 that results in activation of Stat3-responsive genes. We provide evidence that Stat3 is present in the mitochondria ...of cultured cells and primary tissues, including the liver and heart. In Stat3⁻/⁻ cells, the activities of complexes I and II of the electron transport chain (ETC) were significantly decreased. We identified Stat3 mutants that selectively restored the protein's function as a transcription factor or its functions within the ETC. In mice that do not express Stat3 in the heart, there were also selective defects in the activities of complexes I and II of the ETC. These data indicate that Stat3 is required for optimal function of the ETC, which may allow it to orchestrate responses to cellular homeostasis.
Successful curative treatment of severe pulmonary arterial hypertension with luminal obliteration will require a thorough understanding of the mechanism underlying the development and progression of ...pulmonary vascular lesions. But the cells that obliterate the pulmonary arterial lumen in severe pulmonary arterial hypertension are incompletely characterized. The goal of our study was to evaluate whether inhibition of CXC chemokine receptor 4 will prevent the accumulation of c-kit⁺ cells and severe pulmonary arterial hypertension. We detected c-kit⁺⁻ cells expressing endothelial (von Willebrand Factor) or smooth muscle cell/myofibroblast (α-smooth muscle actin) markers in pulmonary arterial lesions of SU5416/chronic hypoxia rats. We found increased expression of CXC chemokine ligand 12 in the lung tissue of SU5416/chronic hypoxia rats. In our prevention study, AMD3100, an inhibitor of the CXC chemokine ligand 12 receptor, CXC chemokine receptor 4, only moderately decreased pulmonary arterial obliteration and pulmonary hypertension in SU5416/chronic hypoxia animals. AMD3100 treatment reduced the number of proliferating c-kit⁺ α-smooth muscle actin⁺ cells and pulmonary arterial muscularization and did not affect c-kit⁺ von Willebrand Factor⁺ cell numbers. Both c-kit⁺ cell types expressed CXC chemokine receptor 4. In conclusion, our data demonstrate that in the SU5416/chronic hypoxia model of severe pulmonary hypertension, the CXC chemokine receptor 4-expressing c-kit⁺ α-smooth muscle actin⁺ cells contribute to pulmonary arterial muscularization. In contrast, vascular lumen obliteration by c-kit⁺ von Willebrand Factor⁺ cells is largely independent of CXC chemokine receptor 4.
Right ventricular (RV) dysfunction (RVD) is the most frequent cause of death in patients with pulmonary arterial hypertension. Although abnormal energy substrate use has been implicated in the ...development of chronic left heart failure, data describing such metabolic remodeling in RVD remain incomplete. Thus, we sought to characterize metabolic gene expression changes and mitochondrial dysfunction in functional and dysfunctional RV hypertrophy.
Two different rat models of RV hypertrophy were studied. The model of RVD (SU5416/hypoxia) exhibited a significantly decreased gene expression of peroxisome proliferator-activated receptor-γ coactivator-1α, peroxisome proliferator-activated receptor-α and estrogen-related receptor-α. The expression of multiple peroxisome proliferator-activated receptor-γ coactivator-1α target genes required for fatty acid oxidation was similarly decreased. Decreased peroxisome proliferator-activated receptor-γ coactivator-1α expression was also associated with a net loss of mitochondrial protein and oxidative capacity. Reduced mitochondrial number was associated with a downregulation of transcription factor A, mitochondrial, and other genes required for mitochondrial biogenesis. Electron microscopy demonstrated that, in RVD tissue, mitochondria had abnormal shape and size. Lastly, respirometric analysis demonstrated that mitochondria isolated from RVD tissue had a significantly reduced ADP-stimulated (state 3) rate for complex I. Conversely, functional RV hypertrophy in the pulmonary artery banding model showed normal expression of peroxisome proliferator-activated receptor-γ coactivator-1α, whereas the expression of fatty acid oxidation genes was either preserved or unregulated. Moreover, pulmonary artery banding-RV tissue exhibited preserved transcription factor A mitochondrial expression and mitochondrial respiration despite elevated RV pressure-overload.
Right ventricular dysfunction, but not functional RV hypertrophy in rats, demonstrates a gene expression profile compatible with a multilevel impairment of fatty acid metabolism and significant mitochondrial dysfunction, partially independent of chronic pressure-overload.
Inflammation and altered immunity are recognized components of severe pulmonary arterial hypertension in human patients and in animal models of PAH. While eicosanoid metabolites of cyclooxygenase and ...lipoxygenase pathways have been identified in the lungs from pulmonary hypertensive animals their role in the pathogenesis of severe angioobliterative PAH has not been examined. Here we investigated whether a cyclooxygenase-2 (COX-2) inhibitor or diethylcarbamazine (DEC), that is known for its 5-lipoxygenase inhibiting and antioxidant actions, modify the development of PAH in the Sugen 5416/hypoxia (SuHx) rat model. The COX-2 inhibitor SC-58125 had little effect on the right ventricular pressure and did not prevent the development of pulmonary angioobliteration. In contrast, DEC blunted the muscularization of pulmonary arterioles and reduced the number of fully obliterated lung vessels. DEC treatment of SuHx rats, after the lung vascular disease had been established, reduced the degree of PAH, the number of obliterated arterioles and the degree of perivascular inflammation. We conclude that the non-specific anti-inflammatory drug DEC affects developing PAH and is partially effective once angioobliterative PAH has been established.
Previous studies have suggested that a high intake of sugar-sweetened beverages is positively associated with the risk of a coronary event. However, a few studies have examined the association ...between sucrose (the most common extrinsic sugar in Sweden) and incident coronary events. The objective of the present study was to examine the associations between sucrose intake and coronary event risk and to determine whether these associations are specific to certain subgroups of the population (i.e. according to physical activity, obesity status, educational level, alcohol consumption, smoking habits, intake of fat and intake of fruits and vegetables). We performed a prospective analysis on 26 190 individuals (62 % women) free from diabetes and without a history of CVD from the Swedish population-based Malmö Diet and Cancer cohort. Over an average of 17 years of follow-up (457 131 person-years), 2493 incident cases of coronary events were identified. Sucrose intake was obtained from an interview-based diet history method, including 7-d records of prepared meals and cold beverages and a 168-item diet questionnaire covering other foods. Participants who consumed >15 % of their energy intake (E%) from sucrose showed a 37 (95 % CI 13, 66) % increased risk of a coronary event compared with the lowest sucrose consumers (<5 E%) after adjusting for potential confounders. The association was not modified by the selected lifestyle factors. The results indicated that sucrose consumption higher than 15 E% (5 % of this population) is associated with an increased risk of a coronary event.
In spite of treatment, severe angioproliferative pulmonary arterial hypertension (PAH) remains a disease characterized by great morbidity and shortened survival. New treatment strategies for patients ...with PAH are needed, and after drug development, preclinical studies are best conducted in animal models which present with pulmonary angio-obliterative disease and right heart failure. A rat model of severe pulmonary hypertension and right heart failure, described a decade ago, continues to be investigated and provide insight into the nature of the lung vascular lesions and mechanisms of cardiac adaptation to an altered lung circulation. This rat model is based on the combination of VEGF receptor blockade with Su5416 and chronic hypoxia; use of this pulmonary hypertension induction strategy led to developing the concept of apoptosis-dependent compensatory vascular cell growth. Although, often employed in experimental designs, chronic hypoxia is not necessary for the development of angio-obliterative pulmonary hypertension. Left pneumonectomy combined with Su5416 also results in severe pulmonary hypertension in normoxic conditions. Similarly, the immune insufficiency component of severe PAH can be modeled in athymic rats (lacking T-lymphocytes). In these rats housed under normoxic conditions, treatment with the VEGFR receptor blocker results in angioproliferative pulmonary hypertension; cardiopulmonary disease in these animals can be prevented by immune reconstitution of regulatory T-cells (Tregs). Finally, chronic hypoxia can be replaced with another stimulator of HIF-1α: Ovalbumin (Ova). Immunization of rats with Ova increases lung tissue HIF-1α protein expression, and in Su5416-treated rats causes lethal pulmonary hypertension. Finally, we postulate that these models may also be useful for “reverse translation”; that is, the mechanisms of lung vascular cell death and growth and the modifying influences of immune and bone marrow cells that have been identified in the Su5416 VEGFR inhibitor models can be informative about heretofore undescribed processes in human PAH.
Background and objectives: MCDA is a decision-making tool with increasing use in the healthcare sector, including HTA (Health Technology Assessment). By applying multiple criteria, including ...innovation, in a comprehensive, structured and explicit manner, MCDA fosters a transparent, participative, consistent decision-making process taking into consideration values of all stakeholders.
This paper by FIFARMA (Latin American Federation of Pharmaceutical Industry) proposes the deliberative (partial) MCDA as a more pragmatic, agile approach, especially when newly implemented.
Methods: Literature review including real-world examples of effective MCDA implementation in healthcare decision making in both the public and private sector worldwide and in LA.
Results and conclusion: It is the view of FIFARMA that MCDA should strongly be considered as a tool to support HTA and broader healthcare decision making such as the contracts and tenders process in order to foster transparency, fairness, and collaboration amongst stakeholders.
The chocolate chip sea cucumber, Isostichopus badionotus (Selenka 1867), is an ecologically and biomedically important species. In this study, we report the complete mitogenome sequence of the sea ...cucumber, I. badionotus (Echinodermata: Holothuroidea). The mitochondrial genome consisted of 16,319 bp, with 13 protein-coding genes, 22 tRNA genes, and 2 rRNA genes. The total nucleotide composition consisted of 31.61% A, 29.20% T, 23.48% C, 15.71% G, with a high A + T content of 60.81%. Phylogenetic analysis using the complete mitochondrial genome of I. badionotus is helpful in studying the evolution of beneficial adaptations to aid in bioremediation and biomedical research and development.
. Hlebowicz J, Persson M, Gullberg B, Sonestedt E, Wallström P, Drake I, Nilsson J, Hedblad B, Wirfält E (Lund University, Skåne University Hospital, Malmö, Sweden). Food patterns, inflammation ...markers and incidence of cardiovascular disease: the Malmö Diet and Cancer study. J Intern Med 2011; 270: 365–376.
Objectives. To examine the associations between food patterns constructed using cluster analysis and markers of systemic and vascular inflammation, and incident cardiovascular disease (CVD) after 13 years of follow‐up.
Design. Population‐based, prospective cohort study.
Setting and subjects. Cluster analysis identified six food patterns from 43 food group variables among 4999 subjects, aged 45–68 years, who participated in the Malmö Diet and Cancer cardiovascular programme between 1991 and 1994. Lipoprotein‐associated phospholipase A2 (Lp‐PLA2), C‐reactive protein concentration and white blood cell (WBC) count were measured using blood samples at baseline. Incidence of CVD (coronary events and ischaemic stroke) was monitored over 13 years of follow‐up.
Results. The fibre‐rich bread pattern was associated with favourable effects on WBC count in women, and the low‐fat and high‐fibre pattern with favourable effects on Lp‐PLA2 mass in women, and on Lp‐PLA2 activity in men. However, the milk fat and sweets and cakes patterns were both associated with adverse effects; the former on WBC count in women and on Lp‐PLA2 mass in men, and the latter on WBC count and Lp‐PLA2 mass in women. The milk fat and sweets and cakes patterns were associated with increased CVD risk in women.
Conclusions. The results of this study support the present Nordic dietary recommendations indicating that diets rich in high‐fibre, low‐fat and low‐sugar foods are favourably associated with markers of inflammation and, potentially, with CVD risk.
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