Proteomics in cardiovascular diseases: Unveiling sex and gender differences in the era of precision medicine

Baetta, Roberta; Pontremoli, Marta; Fernández, Alma Martínez; Spickett, Corinne M.; Banfi, Cristina

doi:10.1016/j.jprot.2017.11.012

Cited by 23 publications

(18 citation statements)

References 167 publications

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“…In the same fashion, the complex cascade mediated by estrogen may lead to changes in coagulation and other systems, accounting for the key role of sex hormone fluctuations in establishing CVD risk, including those occurring during menopause and pregnancy [39,62]. A recent study by Baetta and co-workers [37] clearly reviewed the current status of studies investigating the molecular basis of sex differences in CVD, mainly through the proteomic approach. In this regard, studies on the circulating levels of potential soluble CVD markers have revealed sex-specific differences, such as those in serum levels of the adipocyte fatty acid-binding protein (A-FABP), emerging as a relevant atherosclerosis marker in women (i.e., with different fat distribution and hormonal regulation compared to men), supporting the need for sex/gender-specific biomarkers to be translated in clinical practice [63,64].…”

Section: Women-specific Cvd Risk Factors and Their Molecular Mechanismmentioning

confidence: 99%

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Sex/Gender-Specific Imbalance in CVD: Could Physical Activity Help to Improve Clinical Outcome Targeting CVD Molecular Mechanisms in Women?

Vaccarezza

Papa

Milani

et al. 2020

IJMS

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In the last two decades, new insights have been gained regarding sex/gender-related differences in cardiovascular disease (CVD). CVD represents the leading cause of death worldwide in both men and women, accounting for at least one-third of all deaths in women and half of deaths in women over 50 years in developing countries. Important sex-related differences in prevalence, presentation, management, and outcomes of different CVDs have been recently discovered, demonstrating sex/gender-specific pathophysiologic features in the presentation and prognosis of CVD in men and women. A large amount of evidence has highlighted the role of sex hormones in protecting women from CVDs, providing an advantage over men that is lost when women reach the menopause stage. This hormonal-dependent shift of sex-related CVD risk consequently affects the overall CVD epidemiology, particularly in light of the increasing trend of population aging. The benefits of physical activity have been recognized for a long time as a powerful preventive approach for both CVD prevention and aging-related morbidity control. Exercise training is indeed a potent physiological stimulus, which reduces primary and secondary cardiovascular events. However, the underlying mechanisms of these positive effects, including from a sex/gender perspective, still need to be fully elucidated. The aim of this work is to provide a review of the evidence linking sex/gender-related differences in CVD, including sex/gender-specific molecular mediators, to explore whether sex- and gender-tailored physical activity may be used as an effective tool to prevent CVD and improve clinical outcomes in women.

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Section: Women-specific Cvd Risk Factors and Their Molecular Mechanismmentioning

confidence: 99%

“…Studies aimed at precision medicine are providing increasing data highlighting that it is indeed no longer possible to avoid a proper consideration of sex/gender differences when approaching disease pathophysiology [36][37][38]. Environmental, social, and psychological differences can contribute to sex/gender imbalances in CVD.…”

Section: Introductionmentioning

confidence: 99%

Sex/Gender-Specific Imbalance in CVD: Could Physical Activity Help to Improve Clinical Outcome Targeting CVD Molecular Mechanisms in Women?

Vaccarezza

Papa

Milani

et al. 2020

IJMS

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“…A number of studies have used proteomics to investigate sex differences and overall CVD risk, mostly from biological fluids, such as plasma/serum and urine. 69 In parallel, advancements in the proteomic profiling of atherosclerotic tissue have also occurred. 62 However, as aptly reviewed, studies have yet to focus on identifying sex differences in the atherosclerotic plaque tissue proteome, until "now" (Paper I).…”

Section: "Proteins Are Central To Our Understanding Of Cellular Functmentioning

confidence: 99%

“…62 However, as aptly reviewed, studies have yet to focus on identifying sex differences in the atherosclerotic plaque tissue proteome, until "now" (Paper I). 69…”

Section: "Proteins Are Central To Our Understanding Of Cellular Functmentioning

confidence: 99%

Sex differences in atherosclerosis and exercise effects

Ward

2019

Linköping University Medical Dissertations

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i 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 ...

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“…28 Many studies have demonstrated a gender difference in clinical presentations, diagnosis, treatment, and prevention. 29 Sadly, many women may not always understand the caution and indication signs of a cardiac arrest. An analysis was performed on 515 women patients who experienced an episode or more heart failures disclosed that approximately 43% had not experienced any type of classic signs such as palpitation, arrhythmias, chest pain, shortness of breath, or pressure during the heart attack.…”

Section: Introductionmentioning

confidence: 99%

Novel Variations in β-Myosin Heavy-Chain Gene (β-MYH7) and Its Association in South Indian Women with Cardiomyopathies

et al. 2019

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Background Mutations in β-MYH7 gene is a main genetic cause of cardiomyopathy and sudden cardiac arrest, yet the molecular mechanisms have not been fully understood. Objectives To identify variations in β-MYH7 gene and their possible mechanistic role in cardiomyopathies among Indian women. Methods We sequenced all exons and their flanking regions of the β-MYH7 gene in 188 Indian women consisting of 33 hypertrophic cardiomyopathy (HCM), 48 dilated cardiomyopathy (DCM), and 107 healthy controls. Results Our study showed 21 variations in β-MYH7 gene, including 7 novel mutations. In addition, we compared this dataset with our previously studied datasets of seven other sarcomere genes (ACTC, TNNT2, MYL2, MYBPC3, TPM1, TNNI3, and MYL3) and found no causative mutation, confirming the nonexistence of compound heterozygosity. Interestingly, we detected a Val431Met mutation exclusively in patients, and its pathogenicity has been predicted using the protein homology model. In native, Val431 is evolutionarily conserved across many species. In the homology model, mutant Met431 gets further buried in the hydrophobic core by creating an aberrant hydrophobic interaction with Leu352. As a result, it probably reduces the spatial distances between other hydrophobic interactions in the hydrophobic core that may produce steric hindrance and strain. It may lead to deviation in the structure (root means square deviation [RMSD] of ~3.9), and might possibly causing the cardiac remodeling and cardiomyopathy. Conclusion We identified a novel Val431Met mutation, exclusively in patients, and its homology model p.Met431 has profoundly increased the mechanistic understanding of disease specifically in personalized medicine, to block/inverse/diminish the disease phenotype. AbstractKeywords ► β-MYH7 gene ► homology model ► hypertrophic cardiomyopathy ► dilated cardiomyopathy ► cardiomyopathy

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Proteomics in cardiovascular diseases: Unveiling sex and gender differences in the era of precision medicine

Cited by 23 publications

References 167 publications

Sex/Gender-Specific Imbalance in CVD: Could Physical Activity Help to Improve Clinical Outcome Targeting CVD Molecular Mechanisms in Women?

Sex/Gender-Specific Imbalance in CVD: Could Physical Activity Help to Improve Clinical Outcome Targeting CVD Molecular Mechanisms in Women?

Sex differences in atherosclerosis and exercise effects

Novel Variations in β-Myosin Heavy-Chain Gene (β-MYH7) and Its Association in South Indian Women with Cardiomyopathies

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