Distinct Mitral Valve Proteomic Profiles in Rheumatic Heart Disease and Myxomatous Degeneration

Martins, Carlo; Santos, Keity Souza; Ferreira, Frederico Moraes; Teixeira, Priscila Camillo; Pomerantzeff, Pablo Maria Alberto; Brandão, Carlos Manuel de Almeida; Sampaio, Roney Orismar; Spina, Guilherme Sobreira; Kalil, Jorge; Guilherme, Luiza; Cunha-Neto, Edécio

doi:10.4137/cmc.s17622

Cited by 10 publications

(15 citation statements)

References 41 publications

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“…These include integrin α4β1 (also known as VLA4), intracellular adhesion molecule 1 (ICAM1), P-selectin, CC-chemokine ligand 3 (CCL3; also known as MIP1α), CCL1 (also known as I309) and CXC-chemokine ligand 9 (CXCL9; also known as MIG) 85,113 . The autoimmune reaction in the valves is associated with elevated levels of heart tissue proteins vimentin and lumican and elevated apolipoprotein A1 levels, whereas collagen VI, haptoglobin-related protein, prolargin, biglycan and cartilage oligomeric matrix protein are reduced 125 . This imbalance results in a loss of structural integrity of valve tissue and, consequently, in valve dysfunction.…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Acute rheumatic fever and rheumatic heart disease

Carapetis

Beaton

Cunningham

et al. 2016

Nat Rev Dis Primers

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Acute rheumatic fever (ARF) is the result of an autoimmune response to pharyngitis caused by infection with group A Streptococcus. The long-term damage to cardiac valves caused by ARF, which can result from a single severe episode or from multiple recurrent episodes of the illness, is known as rheumatic heart disease (RHD) and is a notable cause of morbidity and mortality in resource-poor settings around the world. Although our understanding of disease pathogenesis has advanced in recent years, this has not led to dramatic improvements in diagnostic approaches, which are still reliant on clinical features using the Jones Criteria, or treatment practices. Indeed, penicillin has been the mainstay of treatment for decades and there is no other treatment that has been proven to alter the likelihood or the severity of RHD after an episode of ARF. Recent advances — including the use of echocardiographic diagnosis in those with ARF and in screening for early detection of RHD, progress in developing group A streptococcal vaccines and an increased focus on the lived experience of those with RHD and the need to improve quality of life — give cause for optimism that progress will be made in coming years against this neglected disease that affects populations around the world, but is a particular issue for those living in poverty.

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Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Acute rheumatic fever and rheumatic heart disease

Carapetis

Beaton

Cunningham

et al. 2016

Nat Rev Dis Primers

Self Cite

463

486

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“…Apart from cytokines and integrins, the crucial role of ECM protein in RHD is well documented. 22 Herein, we observed a significant expression of vimentin in RHD sera stimulated cells than in control mostly at all time points except at 24h whereas; laminin B, present on the basement membrane of ECs, was mostly upregulated all time intervals [ Fig. 3 A].…”

Section: Resultsmentioning

confidence: 80%

Anti-endothelial cell antibody rich sera from rheumatic heart disease patients induces proinflammatory phenotype and methylation alteration in endothelial cells

et al. 2018

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Rheumatic heart disease (RHD) is a major cause of cardiovascular morbidity and mortality in developing nations like India. RHD commonly affects the mitral valve which is lined by a single layer of endothelial cells (ECs). The role of ECs in mitral valve damage during RHD is not well elucidated. In here, anti-endothelial cell antibody from RHD patients has been used to stimulate the ECs (HUVECs and HMVECs). ECs proinflammatory phenotype with increased expression of TNFα, IL-6, IL-8, IFNγ, IL-1β, ICAM1, VCAM1, E-selectin, laminin B, and vimentin was documented in both ECs. The promoter hypomethylation of various key inflammatory cytokines (TNFα, IL-6, and IL-8), integrin (ICAM1) associated with leukocyte transendothelial migration, and extracellular matrix genes (vimentin, and laminin) were also observed. Further, the in-vitro data was in accordance with ex-vivo observations which correlated significantly with the etiological factors such as smoking, socioeconomic status, and housing. Thus, the study sheds light on the role of ECs in RHD which is a step forward in the elucidation of disease pathogenesis.

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“…Vimentin spots of different molecular weight were previously identified by mass spectrometry in our RHD valvar proteomic study [ 7 ]. Briefly, spots were excised, reduced, alkylated with iodoacetamide, and submitted to controlled proteolysis.…”

Section: Methodsmentioning

confidence: 99%

“…In the present study, we used immunoblot analysis to confirm previous large-scale proteomic analysis [ 7 ], as well as immunohistochemistry and confocal microscopy to assess whether tissue distribution of vimentin, collagen VI, lumican, and vitronectin were also altered in valve-tissue lesions of both RHD and MXD patients as compared to control valve tissue.…”

Section: Introductionmentioning

confidence: 96%

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Rheumatic Heart Disease and Myxomatous Degeneration: Differences and Similarities of Valve Damage Resulting from Autoimmune Reactions and Matrix Disorganization

et al. 2017

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Autoimmune inflammatory reactions leading to rheumatic fever (RF) and rheumatic heart disease (RHD) result from untreated Streptococcus pyogenes throat infections in individuals who exhibit genetic susceptibility. Immune effector mechanisms have been described that lead to heart tissue damage culminating in mitral and aortic valve dysfunctions. In myxomatous valve degeneration (MXD), the mitral valve is also damaged due to non-inflammatory mechanisms. Both diseases are characterized by structural valve disarray and a previous proteomic analysis of them has disclosed a distinct profile of matrix/structural proteins differentially expressed. Given their relevance in organizing valve tissue, we quantitatively evaluated the expression of vimentin, collagen VI, lumican, and vitronectin as well as performed immunohistochemical analysis of their distribution in valve tissue lesions of patients in both diseases. We identified abundant expression of two isoforms of vimentin (45 kDa, 42 kDa) with reduced expression of the full-size protein (54 kDa) in RHD valves. We also found increased vitronectin expression, reduced collagen VI expression and similar lumican expression between RHD and MXD valves. Immunohistochemical analysis indicated disrupted patterns of these proteins in myxomatous degeneration valves and disorganized distribution in rheumatic heart disease valves that correlated with clinical manifestations such as valve regurgitation or stenosis. Confocal microscopy analysis revealed a diverse pattern of distribution of collagen VI and lumican into RHD and MXD valves. Altogether, these results demonstrated distinct patterns of altered valve expression and tissue distribution/organization of structural/matrix proteins that play important pathophysiological roles in both valve diseases.

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Distinct Mitral Valve Proteomic Profiles in Rheumatic Heart Disease and Myxomatous Degeneration

Cited by 10 publications

References 41 publications

Acute rheumatic fever and rheumatic heart disease

Acute rheumatic fever and rheumatic heart disease

Anti-endothelial cell antibody rich sera from rheumatic heart disease patients induces proinflammatory phenotype and methylation alteration in endothelial cells

Rheumatic Heart Disease and Myxomatous Degeneration: Differences and Similarities of Valve Damage Resulting from Autoimmune Reactions and Matrix Disorganization

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