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Sex differences in atherosclerosis and exercise effects
Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cardiovascular disease (CVD) is the leading cause of death globally, with atherosclerosis being the main cause of cardiovascular diseases. Atherosclerosis is an inflammatory disease of the blood vessel wall, which over time will cause thickening and hardening of the vessel wall. Atherosclerosis can result in catastrophic vascular events, such as myocardial infarction and stroke. There are distinct sex differences in CVD mortality at different ages, before menopause women have a lower mortality of CVD in comparison to men, which equalises after menopause. In addition to sex differences in the incidence of CVD, there are also distinct sex differences in the phenotype of atherosclerotic plaques, with men generally developing more severe and vulnerable plaques that are at risk of rupture.

This thesis aimed to investigate the sex differences in atherosclerosis, in particular how the proteome and pathophysiology differs. In addition, we sought to investigate the potential benefit of an exercise programme, in reducing CVD risks, using a randomised controlled trial including postmenopausal women.

Sex differences in atherosclerosis were first investigated via proteomic analysis of human carotid endarterectomy samples. Initially, five intraplaque biopsies were taken from distinct atheroma regions, including; internal control, fatty streak, plaque shoulder, plaque centre, and fibrous cap. Protein extracts from these biopsies were subjected to analysis by mass spectrometry. The novel sampling method was successful in reducing the effect of plaque heterogeneity, a limitation in previous proteomic studies of atherosclerosis, and a number of previously unreported proteins were identified in human carotid atheroma. In addition to this, with the inclusion of multivariate statistical modelling, it was found that 43 proteins significantly discriminated the carotid atheroma between men and women. These proteins were grouped by function, and it was found that atheroma from men was associated with the increased abundance of inflammatory response proteins, including phospholipase-A2 membrane associated and lysozyme C, and atheroma from women was associated with increased abundance of blood coagulation, complement activation, and transport proteins, notably including; antithrombin-III, coagulation factor XII, and afamin. In addition, differences were also ii observed in the abundance of iron metabolism related proteins. These sex differences were further expanded upon from a pathophysiological perspective. Immunohistochemistry stainings of ferritin and transferrin receptor 1 were found significantly increased in the atheroma from men. Moreover, the levels of plasma haemoglobin were also significantly increased in men and were associated with the development of more vulnerable and severe plaque types. The more vulnerable and severe plaque types were also associated with significantly greater macrophage infiltration. In summary, these results are indicative of men developing atheroma with greater inflammation that are more vulnerable, due to increased iron and inflammatory proteins and macrophage infiltration, whereas atheroma from women develop with less inflammation and a more stable phenotype.

The randomised controlled clinical trial aimed at investigating the effects of resistance training (RT), over a 15-week period, in postmenopausal women. Plasma samples were obtained at week-0 and week-15 of the study period, and analyses were performed primarily using a series of immunoassays. Results showed that women participating in RT, with good compliance, were associated with significant decreases in plasma levels of ferritin, lipids, and inflammatory adipokines. These results suggest that the use of regular RT may be a beneficial intervention in reducing the levels of body iron, lipids, and inflammation, all of which are risk factors for the development of CVD. However, validation studies are required in a larger cohort of postmenopausal women, in addition to the inclusion or complementary studies in middle-aged men.

In summary, the works included in this thesis further expand on the current knowledge of sex differences in atherosclerosis, and also provides information on the potential of an exercise intervention to beneficially reduces the effects of known risk factors of CVD.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. , p. 61
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1676
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:liu:diva-156366DOI: 10.3384/diss.diva-156366ISBN: 9789176850978 (print)OAI: oai:DiVA.org:liu-156366DiVA, id: diva2:1305606
Public defence
2019-05-17, Hasselquistsalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2019-04-17 Created: 2019-04-17 Last updated: 2019-04-17Bibliographically approved
List of papers
1. Distinctive proteomic profiles among different regions of human carotid plaques in men and women
Open this publication in new window or tab >>Distinctive proteomic profiles among different regions of human carotid plaques in men and women
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 26231Article in journal (Refereed) Published
Abstract [en]

The heterogeneity of atherosclerotic tissue has limited comprehension in proteomic and metabolomic analyses. To elucidate the functional implications, and differences between genders, of atherosclerotic lesion formation we investigated protein profiles from different regions of human carotid atherosclerotic arteries; internal control, fatty streak, plaque shoulder, plaque centre, and fibrous cap. Proteomic analysis was performed using 2-DE with MALDI-TOF, with validation using nLC-MS/MS. Protein mapping of 2-DE identified 52 unique proteins, including 15 previously unmapped proteins, of which 41 proteins were confirmed by nLC-MS/MS analysis. Expression levels of 18 proteins were significantly altered in plaque regions compared to the internal control region. Nine proteins showed site-specific alterations, irrespective of gender, with clear associations to extracellular matrix remodelling. Five proteins display gender-specific alterations with 2-DE, with two alterations validated by nLC-MS/MS. Gender differences in ferritin light chain and transthyretin were validated using both techniques. Validation of immunohistochemistry confirmed significantly higher levels of ferritin in plaques from male patients. Proteomic analysis of different plaque regions has reduced the effects of plaque heterogeneity, and significant differences in protein expression are determined in specific regions and between genders. These proteomes have functional implications in plaque progression and are of importance in understanding gender differences in atherosclerosis.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-129495 (URN)10.1038/srep26231 (DOI)000376554600001 ()27198765 (PubMedID)
Note

Funding Agencies|Swedish Heart Lung Foundation; Linkoping University Hospital Research foundation; Swedish Institute; China Scholarship Council

Available from: 2016-06-20 Created: 2016-06-20 Last updated: 2019-04-17
2. Proteomics and multivariate modelling reveal sex-specific alterations in distinct regions of human carotid atheroma
Open this publication in new window or tab >>Proteomics and multivariate modelling reveal sex-specific alterations in distinct regions of human carotid atheroma
2018 (English)In: Biology of Sex Differences, ISSN 2042-6410, Vol. 9, article id 54Article in journal (Refereed) Published
Abstract [en]

BackgroundAtherosclerotic lesions are comprised of distinct regions with different proteomic profiles. Men and women develop differences in lesion phenotype, with lesions from women generally being more stable and less prone to rupture. We aimed to investigate the differences in proteomic profiles between sexes, including distinct lesion regions, to identify altered proteins that contribute to these differences observed clinically.MethodsCarotid endarterectomy samples (ten men/ten women) were obtained, and intraplaque biopsies from three distinct regions (internal control, fatty streak and plaque) were analysed by tandem-mass spectrometry. Multivariate statistical modelling, using orthogonal partial least square-discriminant analysis, was used to discriminate the proteomes between men and women.ResultsMultivariate discriminant modelling revealed proteins from 16 functional groups that displayed sex-specific associations. Additional statistics revealed ten proteins that display region-specific alterations when comparing sexes, including proteins related to inflammatory response, response to reactive oxygen species, complement activation, transport and blood coagulation. Transport protein afamin and blood coagulation proteins antithrombin-III and coagulation factor XII were significantly increased in plaque region from women. Inflammatory response proteins lysozyme C and phospholipase A2 membrane-associated were significantly increased in plaque region from men. Limitations with this study are the small sample size, limited patient information and lack of complementary histology to control for cell type differences between sexes.ConclusionsThis pilot study, for the first time, utilises a multivariate proteomic approach to investigate sexual dimorphism in human atherosclerotic tissue, and provides an essential proteomic platform for further investigations to help understand sexual dimorphism and plaque vulnerability in atherosclerosis.

Place, publisher, year, edition, pages
BMC, 2018
Keywords
Afamin; Atherosclerosis; Lysozyme C; Mass spectrometry; Serine protease inhibitors; Vulnerability
National Category
Medical Genetics
Identifiers
urn:nbn:se:liu:diva-153822 (URN)10.1186/s13293-018-0217-3 (DOI)000454616000001 ()30594242 (PubMedID)
Note

Funding Agencies|Swedish Heart Lung Foundation; Torsten and Ragnar Soderbergs Foundation; Stroke Foundation; Olle Engkvist Foundation; Swedish Gamla Tjanarinnor Foundation; Linkoping University Hospital Research Fund

Available from: 2019-01-11 Created: 2019-01-11 Last updated: 2019-05-02
3. Carotid Atheroma From Men Has Significantly Higher Levels of Inflammation and Iron Metabolism Enabled by Macrophages
Open this publication in new window or tab >>Carotid Atheroma From Men Has Significantly Higher Levels of Inflammation and Iron Metabolism Enabled by Macrophages
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2018 (English)In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 49, no 2, p. 419-425Article in journal (Refereed) Published
Abstract [en]

Background and Purpose-Men differ from women in the manifestation of atherosclerosis and iron metabolism. Intraplaque hemorrhage and hemoglobin (Hb) catabolism by macrophages are associated with atherosclerotic lesion instability. The study aims were to investigate sex differences in (1) lesion severity in relation to blood Hb, (2) iron homeostasis in human carotid plaques, and (3) macrophage polarization within atheroma. Methods-The carotid artery samples from 39 men and 23 women were immunostained with cell markers for macrophages, smooth muscle cells, ferritin, and TfR1 (transferrin receptor 1), which were further analyzed according to sex in relation to iron, Hb, and lipids in circulation. Additionally, samples of predefined regions from human carotid atherosclerotic lesions, including internal controls, were used for proteomic analysis by mass spectrometry. Results-Male patients, compared with women, had larger necrotic cores and more plaque rupture, which were associated with higher levels of Hb. Atheroma of male patients had significantly higher levels of Hb in circulation and CD68 macrophages, ferritin, and TfR1 in lesions. CD68 macrophages were significantly correlated with ferritin and TfR1. Plaques from male patients comparatively possessed higher levels of inflammatory macrophage subsets, CD86 (M1) and CD163 (M2), but lower levels of STF (serotransferrin) and HPX (hemopexin). Conclusions-Male patients with carotid atheroma had more advanced and ruptured lesions associated with significantly higher levels of inflammatory macrophage infiltration and high iron stores in the blood and in their plaques. These findings help to understand sex differences and iron metabolism in atherosclerosis and factors related to atheroma progression.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2018
Keywords
atherosclerosis; ferritins; hemoglobins; hemopexin; macrophages; male
National Category
Neurology
Identifiers
urn:nbn:se:liu:diva-144876 (URN)10.1161/STROKEAHA.117.018724 (DOI)000422928000035 ()29284736 (PubMedID)
Note

Funding Agencies|Swedish Heart-Lung Foundation; Torsten and Ragnar Soderbergs Foundation; Stroke Foundation; Olle Engkvist Foundation; Swedish Gamla Tjanarinnor Foundation; Linkoping University; Linkoping University Hospital Research Fund

Available from: 2018-02-09 Created: 2018-02-09 Last updated: 2019-05-02

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