Cardiovascular disease is the leading cause of death in women. Although overall mortality from coronary heart disease (CHD) has decreased, there are subsets of patients, particularly youngwomen, in whom the mortality rate has increased. Underlying sex differences in CHD may be an explanation. Women have more frequent symptoms, more ischemia, and higher mortality than men, but less obstructive coronary artery disease (CAD). Despite this, traditional risk factor assessment has been ineffective in risk stratifying women, prompting the emergence of novel markers and prediction scores to identify a population at risk. Sex differences inmanifestations and the pathophysiology of CHD also have led to differences in the selection of diagnostic testing and treatment options for women, having profound effects on outcomes. The frequent finding of nonobstructive CAD in women with ischemia suggests microvascular dysfunction as an underlying cause; therefore, coronary reactivity and endothelial function testing may add to diagnostic accuracy in female patients. In spite of evidence that women benefit from the same therapies as men, they continue to receive lessaggressive therapy, which is reflected in higher healthcare resource utilization and adverse outcomes. More sex-specific research is needed in the area of symptomatic nonobstructive CAD to define the optimal therapeutic approach.

Cardiovascular disease is the leading cause of death in women. Although overall mortality from coronary heart disease (CHD) has decreased, there are subsets of patients, particularly youngwomen, in whom the mortality rate has increased. Underlying sex differences in CHD may be an explanation. Women have more frequent symptoms, more ischemia, and higher mortality than men, but less obstructive coronary artery disease (CAD). Despite this, traditional risk factor assessment has been ineffective in risk stratifying women, prompting the emergence of novel markers and prediction scores to identify a population at risk. Sex differences inmanifestations and the pathophysiology of CHD also have led to differences in the selection of diagnostic testing and treatment options for women, having profound effects on outcomes. The frequent finding of nonobstructive CAD in women with ischemia suggests microvascular dysfunction as an underlying cause; therefore, coronary reactivity and endothelial function testing may add to diagnostic accuracy in female patients. In spite of evidence that women benefit from the same therapies as men, they continue to receive lessaggressive therapy, which is reflected in higher healthcare resource utilization and adverse outcomes. More sex-specific research is needed in the area of symptomatic nonobstructive CAD to define the optimal therapeutic approach.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12999号 / 論医博第2107号 / 新制||医||1016(附属図書館) / 32927 / (主査)教授 川上 浩司, 教授 古川 壽亮, 教授 小池 薫 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21421号 / 医博第4411号 / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 瀬原 淳子, 教授 木村 剛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Monocyte chemotactic protein-1 (MCP-1) plays a critical role in the development of cardiovascular diseases. How MCP-1 contributes to the development of heart disease is not understood. We present evidence that MCP-1 causes death in cardiac myoblasts, H9c2 by inducing oxidative stress, ER stress and autophagy via a novel Znfinger protein, MCP-1 induced protein (MCPIP). MCPIP expression caused cell death and knockdown of MCPIP, attenuated MCP-1 induced cell death. Expression of MCPIP resulted in induction of iNOS and production of reactive oxygen (ROS). It caused induction of NADPH oxidase subunit phox47 and its translocation to the cytoplasmic membrane. Oxidative stress led to the induction of ER stress markers HSP40, PDI, GRP78 and IRE1α. ER stress lead to autophagy as indicated by beclin-1 induction, cleavage of LC3 to LCII and autophagolysosome formation. Here, MCPIP-induced processes lead to apoptosis as indicated by caspase 3 activation and TUNEL assay. This cell death involved caspase 2 and caspase 12 as specific inhibitors of these caspases prevented MCPIP-induced cell death. Inhibitors of oxidative stress inhibited ER stress, and cell death. Specific inhibitors of ER stress inhibited autophagy and cell death. Inhibition of autophagy inhibited cell death. Microarray analysis showed that MCPIP expression caused induction of a variety of genes known to be involved in cell death. MCPIP caused activation of JNK and p38 and induction of p53 and PUMA. These results collectively suggest that MCPIP induces ROS/RNS production that causes ER stress which leads to autophagy and apoptosis through caspase 2/12 and IRE1α –JNK/p38-p53-PUMA pathway. These results provide the first molecular insights into the mechanism by which elevated MCP-1 levels associated with chronic inflammation may contribute to the development of heart failure. A role for inflammation and MCP-1 in obesity and diabetes has been implicated. Adipogenesis is a key process involved in obesity and associated diseases such as type 2 diabetes. This process involves temporally regulated genes controlled by a set of transcription factors, C/EBPβ, C/EBPδ, C/EBPα, and PPARγ. Currently PPARγ is considered the master regulator of adipogenesis as no known factor can induce adipogenesis without PPARγ. We present evidence that a novel Zn-finger protein, MCPIP, can induce adipogenesis without PPARγ. Classical adipogenesis-inducing medium induces MCP-1 production and MCPIP expression in 3T3-L1 cells before the induction of the C/EBP family of transcription factors and PPARγ. Knockdown of MCPIP prevents their expression and adipogenesis. Treatment of 3T3-L1 cells with MCP-1 or forced expression of MCPIP induces expression of C/EBPβ, C/EBPδ, C/EBPα, PPARγ and adipogenesis without any other inducer. Forced expression of MCPIP induces adipogenesis in PPARγ-/- fibroblasts. Thus, MCPIP is a newly identified master controller that can induce adipogenesis without PPARγ. Heart failure is a major cause of death in diabetic patients. Hyperglycemia is a major factor associated with diabetes that causes cardiomyocyte apoptosis that leads to diabetic cardiomyopathy. Cardiomyoycte apoptosis is a key event involved in the pathophysiological progression of diabetic cardiomyopathy. We have recently found that in ischemic hearts, MCP-1 can induce the zinc-finger protein, MCP-1 induced protein (MCPIP) that causes cardiomyocyte apoptosis. Although there is evidence that inflammation may play a role in diabetic cardiomyopathy, the underlying mechanisms are poorly understood. In this study, we show that treatment of H9c2 cardiomyoblasts and Neonatal Rat Ventricular Myocytes (NRVM) with 28mmol/L glucose concentration results in the induction of both transcript and protein levels of MCP-1 and MCPIP. Inhibition of MCP-1 interaction with CCR2 via specific antibody or with the G-coupled receptor inhibitors propagermanium and pertussis toxin attenuated glucose-induced cell death. Knockdown of MCPIP with specific siRNA yielded similar results. Treatment of cells with 28mmol/L glucose resulted in increased ROS production and phox47 activation. Knockdown of MCPIP attenuated these effects. The increased ROS production observed in H9c2 cardiomyoblasts and NRVM's resulted in increased ER stress proteins GRP78 and PDI. Knockdown of MCPIP attenuated expression of both GRP78 and PDI. Inhibition of ER stress with TUDC and 4'PBA prevented high glucoseinduced cell death death. Treatment of cells with 28mmol/l glucose resulted in autophagy as determined by an increase in expression of beclin-1 and through increased cleavage of LC3I to LC3II. Knockdown of MCPIP attenuated expression of beclin-1 and prevented cleavage of LC3. Addition of the autophagy inhibitors 3'methyladenine and LY294002 attenuated high glucose-induced H9c2 cardiomyoblast death. We conclude that high glucose-induced H9c2 cardiomyoblast death is mediated via MCP-1 induction of MCPIP that results in ROS that leads to ER stress that causes autophagy and eventual apoptosis.

No description available.

L’objectif est de tester les associations de marqueurs inflammatoires et lipidiques avec la survenue de cardiopathies ischémiques chez la personne âgée non institutionnalisée. Les analyses sont menées dans une étude cas cohorte dans le cadre de l’étude des 3 Cités. Elle inclut 199 sujets ayant développé un premier évènement coronaire sur 4 ans de suivi et 1086 sujets sans antécédents cardiovasculaires (sous cohorte). Un premier travail suggère que la protéine C-réactive (CRP-US) est un marqueur de risque indépendant des évènements coronaires (risque relatif standardisé du log de la CRP-US=1,27 ; IC95%=1,08-1,64) mais n’améliore pas la prédiction du risque coronaire. Le second travail démontre une hétérogénéité dans l’association des lipides classiques et des apolipoprotéines avec les évènements coronaires selon la prise et la nature du traitement hypolipémiant à l’inclusion. Le troisième travail indique que les apolipoprotéines AI et B100 mais pas le non-HDL cholestérol améliorent significativement la prédiction du risque coronaire sur la base d’indice de reclassification. / The aim was investigate associations of inflammatory and lipids markers with occurrence of ischaemic heart disease (IHD) in community dwelling elderly subjects. Within the Three City Study, a case cohort study was used including 199 subjects with first coronary events over 4 years and 1086 participants free from prevalent cardiovascular disease (random sample). The first paper showed that C-reactive protein was independently associated with IHD (standardized hazard ratio of log CRP-US=1.27; CI95%=1.08-1.64) but did not improve IHD risk prediction beyond usual risk factors. The second paper showed heterogeneity in the association between lipids and apolipoproteins with IHD depending on the use and the type of lipid-lowering therapy (statins or fibrates). Using imputations and reclassification metrics, the third paper suggests that apolipoproteins AI and B100 added significant predictive information beyond usual risk factors for IHD risk prediction.

La cellule est susceptible de modifier l'expression de ces gènes en fonction de son environnement. Dans les cellules eucaryotes, la régulation de l'expression de ces gènes se présente dans plusieurs étapes. Cette régulation peut intervenir dès la transcription de l'ADN jusqu'au devenir des transcrits. La régulation post-transcriptionnelle tient un rôle déterminant dans la synthèse protéique. Elle regroupe l'ensemble des contrôles qui s'exercent sur les transcrits. Cette régulation est induite en réponse à différents stimuli comme la différenciation ou lors de stress cellulaires. En situation de stress, la traduction canonique dépendante de la coiffe est bloquée, à l'exception de certains ARNm essentiels pour assurer la survie des cellules. De ce fait, les cellules mettent en place un mécanisme alternatif afin de continuer la traduction. Un des mécanismes de traduction, implique le site d'entrée interne du ribosome ou IRES (Internal Ribosome Entry Site). L'IRES est une séquence en structure secondaire dans la partie 5' non-traduite de certains ARNm. Il existe des facteurs responsables de leur activation appelés ITAF ou IRES-transacting factor, permettant le recrutement des ribosomes pour initier la traduction. Les protéines pouvant se lier aux ARN sont les acteurs majeurs de l'activation des IRES. Mon travail de thèse est d'étudier les régulateurs post-transcriptionnels en réponse à différents stimuli par le biais de la traduction IRES-dépendante. Dans la première partie de mon projet, nous avons montré la régulation de la traduction via l'activation de l'IRES du FGF1 et ce de manière promoteur-dépendante au cours de la différenciation des myoblastes. Grâce à la technique de résonance plasmonique de surface (SPR) nous avons découvert deux protéines p54nrb/NONO et hnRNPM en tant qu'ITAF capables de former un complexe pour activer l'IRES du FGF1 durant la différenciation des myoblastes. Dans la deuxième partie de ma thèse, nous avons démontré l'existence de l'IRES du VEGFD durant un choc thermique dans les cellules cancéreuses. Nous avons aussi découvert que cette activation est médiée par un ITAF qui est la nucléoline, jamais démontrée auparavant comme ITAF de l'IRES du VEGFD. D'après nos résultats, le stress thermique induit la délocalisation de la nucléoline du noyau vers le cytoplasme pour changer la conformation de l'IRES du VEGFD afin de continuer sa traduction. Dans la troisième partie de mon projet, j'ai étudié de manière générale la régulation des gènes angiogéniques et lymphangiogéniques. L'ensemble des données montre que ces gènes sont majoritairement régulés au niveau traductionnel dans les cardiomyocytes en condition hypoxique. En étudiant les IRES angiogéniques et lymphangiogéniques, nos résultats montrent l'activation de ces IRES à différents temps au cours de l'hypoxie précoce. Dans la même condition, nous avons découvert la protéine vasohibin-1 comme ITAF hypoxique et spécifique de l'IRES du FGF1 dans les cardiomyocytes. En conclusion, nous avons découvert différents ITAF spécifiques à un IRES et en fonction du stress. P54nrb/NONO, hnRNPM sont des ITAF de l'IRES du FGF1 durant la différenciation cellulaire et la vasohibine-1 en hypoxie dans les cardiomyocytes. La nucléoline permet d'activer un IRES du VEGFD en réponse au choc thermique. / In cell, gene expression can be modified depending on the cellular microenvironment. Regulation of gene expression occurs at different levels, ranging from the transcription of the DNA to the mRNA. Among the post- transcriptional regulation, the control of translation plays a crucial role. In particular, the translational regulation occurs in response to different stimuli such as cell differentiation or cell stress. In stress condition, the canonical cap-dependent translation is blocked, excepted some mRNAs that are translated by alternative mechanisms. One of these mechanisms involves the structural elements of the mRNAs, the IRES (Internal Ribosome Entry Sites). The IRES activation involves some factors called ITAFs (IRES trans-acting factors), which allow the internal recruitement of ribosomes to initiate translation. My thesis is to study the mechanisms of IRES-dependent translation regulation in response to different stimuli, and to identify ITAFs responsible for this regulation. In the first part of my project, we have shown that the translation controlled by the FGF1 mRNA IRES is activated. This activation depends on its own promoter during the early phase of murine myoblast differentiation. Through biomolecular interaction analysis technology by surface plasmon resonance coupled to mass spectrometry (BIA/MS), we identified two proteins, p54nrb/NONO and hnRNPM bound both to the IRES and the FGF1gene promoter. These two proteins are both ITAFs activators of IRES and activators of FGF1 promoter transcription, resulting in a coupling of transcription and translation responsible for the induction of the FGF1 expression during myoblast differentiation. In the second part of this thesis, we demonstrated the existence of an IRES within the VEGFD mRNA. This IRES is activated by heat shock in mammary murine carcinoma. BIA/MS technology has enabled us to identify nucleolin as ITAF responsible for this activation. SHAPE experiments revealed the presence of two alternative structures of VEGFD IRES. According to our results, the heat shock induced the relocation of nucleolin from the nucleus to the cytoplasm, suggesting its binding to the mRNA in the cytoplasm could stabilize the conformation of the mRNA VEGFD IRES and activate its translation. The third part of my thesis focused on translational regulation of lymphangiogenic and angiogenic genes into cardiomyocytes in hypoxic conditions. The data obtained by the semi-global approach Fluidigm indicate that only few genes are induced at the transcriptional level, while the majority of them, especially those which have the mRNA IRES, are activated at translational level in hypoxic cardiomyocytes. I have also shown that the mRNA IRES of factors (lymph)angiogenic VEGF and FGF are activated during early hypoxia. Through Technology BIA/MS, I identified a specific hypoxic ITAF of FGF1 IRES in cardiomyocytes: it is the vasohibin - 1 protein involved in angiogenesis and stress tolerance. So, my thesis has enabled to make progress in understanding the mechanisms of IRES-dependent translation regulation. In addition, I have demonstrated that in cardiomyocytes during hypoxia the gene expression is surprisingly regulated at translational level. My work led to the identification of several molecular actors responsible for the regulation of mRNA (lymph)angiogenic factors translation, which could play a key role in ischemic pathologies and in cancer, and provide new targets therapeutic.

Introduction: Transcatheter aortic valve implantation (TAVI) is an established procedure to treat severe aortic stenosis (AS). This study investigates the impact of ischemic heart disease (IHD) on survival in patients undergoing TAVI. Aim: Five-year all-cause mortality stratified according to the presence or absence of IHD. Methods: Retrospective register study including all patients that underwent a TAVI-procedure 2009 to 2018. Patients were stratified according to the presence or absence of IHD. Our primary end-point was five-year all-cause mortality. Survival was analyzed using Kaplan-Meier curve. Data were acquired through the SWENTRY registry and patient files. Results: A total of 264 patients were included in the study, with 139 (52.7 %) patients in the IHD group vs 125 (47.3 %) patients in the non-IHD group. Mean follow-up time was 40 ±30 months. At baseline, there was a higher proportion of males, patients with hypertension, peripheral arterial disease, left ventricular ejection fraction <50 % and, a higher EuroSCORE I in the IHD-group. Transfemoral approach was most common in both groups. No differences were noted in respect to peri- and postoperative complications. Five-year all-cause mortality was 17/38 (44.7 %) vs 18/30 (60.0 %), p = 0,232, in the IHD and non-IHD group respectively. Non-adjusted cumulative five-year survival was not significantly different between the groups (Log-Rank, p = 0,056). Conclusions: In patients with severe AS undergoing TAVI, the five-year all-cause mortality was not statistically different between patients with or without IHD.

Darbo problema – vis dar lieka neaiškus PRR efektyvumas ir jos sąsajos su amžiumi, lytimi, išsilavinimu, IŠL forma, subjektyvia savijauta, subjektyviu sveikatos vertinimu bei organizmo raumenų įtampa, sergantiems IŠL. Todėl šio tyrimo tikslas - nustatyti progresuojančios raumenų relaksacijos taikymo efektyvumą AKS reguliavimui, atsižvelgiant į lytį, amžių, ligos formą, subjektyvų sveikatos vertinimą, išsilavinimą, raumenų įtampą ir subjektyvią savijautos įtampą, sergantiems IŠL, stacionarinės reabilitacijos etape. Tyrime buvo pakviesti dalyvauti 204 Abromiškių reabilitacinės ligoninės, kardiologinio skyriaus pacientai, tačiau į 1 užsiėmimą atėjo 53 (48,18 %) vyrai ir 40 (42,55 %) moterų, į 2 – 20 (18,18 %) vyrų ir 14 (14,89 %) moterų, į 3 – 15 (13,63 %) vyrų ir 12 (12,76 %) moterų ir į 4 – 12 (10,9 %) vyrų ir 8 (8,51 %) moterys. Tiriamieji dalyvavo 4 vienos valandos užsiėmimuose, kurie vyko 4 kartus per savaitę. Siekiant įvertinti PRR efektyvumą AKS mažinimui ir efektyvumo sąsajas su prieš tai išvardintais faktoriais, tiriamiesiems buvo pateikiamos anketos, vedami relaksaciniai užsiėmimai. Kiekvieno užsiėmimo pradžioje ir pabaigoje buvo matuojamas AKS ir duodamas užpildyti manekenas (raumenų įtampai įvertinti) bei subjektyvios savijautos skalė. Tyrimo rezultatai parodė, kad po relaksacijos AKS statistiškai reikšmingi sumažėjimai buvo tik vyrų tarpe, taip pat tarp jaunesnių pacientų, žmonėms sergantiems lengvesne IŠL forma, pacientams su aukštuoju išsilavinimu ir blogesniu... [toliau žr. visą tekstą] / It is still unclear if effectiveness of PMR is related with age, gender, education, IHD form, subjective health status, subjective tension and muscle tension for ischemic heart disease patients. So the aim of this survey is to analize how effectiveness of progressive muscle relaxation in blood pressure regulation is related with these factors for ischemic heart disease in-patients at their rehabilitation period. 204 patients from Abromiškės rehabilitation hospital, cardiac department were invited to participate in relaxation groups, but in the first group participated only 53 (48,18%) men and 40 (42,55%) women, in the second - 20 (18,18%) men and 14 (14,89%) women, in the third - 15 (13,63%) men and 12 (12,76%) women and in fourth - 12 (10,9%) men and 8 (8,51%) women. Participants attended in four hourly relaxation groups which were four times per week. With the purpose to evaluate PMR effectiveness for blood pressure regulation and its’ relation with factors, participants were given questionnaires also relaxation groups were provided. At the beginning and at the end of each session blood pressure was measured also muscle tension was evaluated with the given model and 10 score scale was given for subjective feeling evaluation. The results of this study showed that the statistically significant reductions of blood pressure were only for men also for younger patients and patients with higher education, for patients with easier IHD form and for patients with worse... [to full text]