Complement system is activated in stenotic aortic valves

Helske, Satu; Oksjoki, Riina; Lindstedt, Ken A.; Lommi, Jyri; Turto, Heikki; Werkkala, Kalervo; Kupari, Markku; Kovanen, Petri T.

doi:10.1016/j.atherosclerosis.2007.03.040

Cited by 49 publications

(43 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Complement activation in aortic stenosis has already been detected before,34 but in the present study we were able to show close scrutiny of the staining patterns of complement components with eLDL for the first time, and our semiquantitative immunohistochemical analysis of eLDL and C5b‐9 suggests that C5b‐9 deposits reflect the presence of extensively modified LDL, whereby other possible complement activating mechanisms are not excluded. The significance of local complement activation itself can hardly be overemphasized.…”

Section: Discussionsupporting

confidence: 62%

“…The significance of local complement activation itself can hardly be overemphasized. Complement plays a role in promoting the progression of cardiovascular disease, for example by acting as a drive to inflammation by increasing secretion of monocyte chemotactic protein‐1 and/or interleukin‐8 34, 35. Possible targets for sublytic complement attack in aortic valve sclerosis are VICs/myofibroblasts, the main cell type of the aortic valve (Figure 6A) 36…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Enzymatically Modified Low‐Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease

Twardowski

Cheng

Michaelsen

et al. 2015

JAHA

View full text Add to dashboard Cite

BackgroundWe have demonstrated previously that enzymatically degraded low‐density lipoprotein (eLDL) is an essential causative component for the initiation of atherosclerosis. Here, we investigated the different stages of human aortic valve sclerosis for the presence of eLDL and effectors of the innate immune system, as well as the interaction of eLDL with isolated valvular interstitial cells/myofibroblasts to discover possible pathways leading to aortic valve sclerosis.Methods and ResultsHuman aortic valvular tissue was obtained from 68 patients undergoing valve replacement surgery. Patients were classified into 3 groups (mild, moderate, or severe aortic valve sclerosis), and clinical data for statistical analysis were gathered from all patients. Immunohistochemical staining demonstrated extensive extracellular deposits of eLDL throughout all grades of aortic valve sclerosis. Complementary analysis of lipid composition revealed higher concentrations of the decisive components of eLDL (ie, unesterified cholesterol and linoleic acid) compared with internal control tissues. Further, the complement component C3d and terminal complement complexes colocalized with eLDL compatible with the proposal that subendothelially deposited eLDL is enzymatically transformed into a complement activator at early stages of valvular cusp lesion development. Gene expression profiles of proteases and complement components corroborated by immunohistochemistry demonstrated an upregulation of the protease cathepsin D (a possible candidate for LDL degradation to eLDL) and the complement inhibitor CD55. Surprisingly, substantial C‐reactive protein expression was not observed before grade 2 aortic valve sclerosis as investigated with microarray analysis, reverse transcription–polymerase chain reaction analysis, and immunohistochemistry. Finally, we demonstrated cellular uptake of eLDL by valvular interstitial cells/myofibroblasts.ConclusionsThe present study is a startup of a hypothesis on the pathogenesis of aortic valve sclerosis declaring extracellular lipoprotein modification, subsequent complement activation, and cellular uptake by valvular interstitial cells/myofibroblasts as integral players.

show abstract

Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Enzymatically Modified Low‐Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease

Twardowski

Cheng

Michaelsen

et al. 2015

JAHA

View full text Add to dashboard Cite

show abstract

“…39 In stenotic aortic valves, the complement system is also activated, leading to C3a generation, which induces an inflammatory response in myofibroblasts. 40 Recently, Hage et al 41 found that, in injured mouse carotid arteries, C-reactive protein induces exaggeration of neointima formation, associated with increased C3 deposition in the surrounding adventitia. In this study, we demonstrated that the DOCA-salt hypertensive model showed increased C3 expression in perivascular tissue, which associated with adventitial thickening and myofibroblast clustering around PVAT.…”

Section: Discussionmentioning

confidence: 99%

Perivascular Adipose Tissue–Derived Complement 3 Is Required for Adventitial Fibroblast Functions and Adventitial Remodeling in Deoxycorticosterone Acetate–Salt Hypertensive Rats

Ruan

Zhu

Chen

et al. 2010

ATVB

View full text Add to dashboard Cite

Objective-To examine the role of perivascular adipose tissue (PVAT)-derived factors in the regulation of adventitial fibroblast (AF) function in vitro and in vivo. Methods and Results-PVAT is an active component of blood vessels. Bioactive substances released from PVAT play regulatory roles in vascular function. However, their effects on vascular AFs remain unclear. PVAT-conditioned medium stimulated AF migration using a transwell technique, and differentiation was evaluated by ␣-smooth muscle-actin induction. We identified the secretome of PVAT by liquid chromatography-tandem mass spectrometry. One of the major secretory proteins in PVAT is complement 3 (C3). The C3 antagonist and neutralizing antibody attenuated PVAT-conditioned medium-induced AF migration and differentiation. Similar to PVAT-conditioned medium, C3 recombinant protein stimulated AF migration and differentiation. We demonstrated that the effects of PVAT-derived C3 were mediated by the c-Jun N-terminal kinase pathway. Moreover, we found morphological changes in perivascular adipocytes and increased expression of C3 in PVAT that was tightly associated with adventitial thickening and myofibroblast clustering around PVAT in deoxycorticosterone acetate-salt hypertensive rats. Key Words: perivascular adipose tissue Ⅲ migration Ⅲ ␣-smooth muscle actin Ⅲ complement 3 Ⅲ hypertensive rats Ⅲ adventitial fibroblasts A lmost all blood vessels are surrounded by perivascular adipose tissue (PVAT), which has been considered merely a structural support for vasculature. Recent studies revealed that PVAT produced and released various bioactive substances, playing a dual role in the regulation of vascular function. 1 Adipocyte-derived relaxing factors released from PVAT have attenuated the contractile response of rat aorta responding to norepinephrine. 2,3 However, PVAT also promoted vasoconstriction through production of superoxide and inflammatory cytokines, such as tumor necrosis factor ␣ (TNF␣) and interleukin 6. 4,5 In particular, the conditioned medium of PVAT induced vascular smooth muscle cell (VSMC) proliferation through activation of mitogen-activated protein kinase (MAPK) pathways via paracrine adipokines. 6,7 In pathophysiologic processes of vascular remodeling, phenotypic changes in perivascular cells correlated with upregulation of proinflammatory adipocytokines, which may contribute to vascular dysfunction. 8,9 The list of bioactive factors released from PVAT is increasing, and the role of these adipocytokines in the regulation of vascular function is being unraveled. 10,11 Multiple lines of evidence suggest that vascular adventitial fibroblasts (AFs), the major cell component of adventitia, play a vital role in regulating the structure and function of blood vessels. 12,13 Previous studies 14,15 indicated that numerous active cytokines induce AF migration, which may be associated with the pathogenesis of neointimal formation. Although AFs are in closer proximity to PVAT compared with VSMCs, little attention has been devoted to the role of PVAT-der...

show abstract

“…Further support for the role of cholesterol in AS progression originates from animal models, in which hypercholesterolemia increased aortic valve cholesterol content and induced bone matrix production and calcification of the valves, which could be inhibited by statin treatment (9,10). Besides increasing valvular lesion size and promoting the entry of cholesterol in the affected valves, locally accumulated plant sterols could accentuate inflammation in the valves, which is a key element in lesion development and contributes to valve calcification and progression of the disease (5,(40)(41)(42)(43)(44)(45)(46). Interestingly, plant sterols are more avidly oxidized than cholesterol in serum (47), suggesting that oxidized plant sterols, like oxidized cholesterol, could serve as triggers of inflammation in aortic valves (48).…”

Section: Discussionmentioning

confidence: 99%

Accumulation of cholesterol precursors and plant sterols in human stenotic aortic valves

Helske

Miettinen

Gylling

et al. 2008

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

The pathogenesis of aortic valve stenosis (AS) is characterized by the accumulation of LDL-derived cholesterol in the diseased valves. Since LDL particles also contain plant sterols, we investigated whether plant sterols accumulate in aortic valve lesions. Serum samples were collected from 82 patients with severe AS and from 12 control subjects. Aortic valves were obtained from a subpopulation of 21 AS patients undergoing valve surgery and from 10 controls. Serum and valvular total cholesterol and noncholesterol sterols were measured by gas-liquid chromatography. Noncholesterol sterols, including both cholesterol precursors and sterols reflecting cholesterol absorption, were detected in serum samples and aortic valves. The higher the ratios to cholesterol of the cholesterol precursors and absorption markers in serum, the higher their ratios in the stenotic aortic valves (r 5 0.74, P , 0.001 for lathosterol and r 5 0.88, P , 0.001 for campesterol). The valvular ratio to cholesterol of lathosterol correlated negatively with the aortic valve area (r 5 20.47, P 5 0.045), suggesting attenuation of cholesterol synthesis with increasing severity of AS. The higher the absorption of cholesterol, the higher the plant sterol contents in stenotic aortic valves. These findings suggest that local accumulation of plant sterols and cholesterol precursors may participate in the pathobiology of aortic valve disease.

show abstract

Complement system is activated in stenotic aortic valves

Cited by 49 publications

References 45 publications

Enzymatically Modified Low‐Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease

Enzymatically Modified Low‐Density Lipoprotein Is Present in All Stages of Aortic Valve Sclerosis: Implications for Pathogenesis of the Disease

Perivascular Adipose Tissue–Derived Complement 3 Is Required for Adventitial Fibroblast Functions and Adventitial Remodeling in Deoxycorticosterone Acetate–Salt Hypertensive Rats

Accumulation of cholesterol precursors and plant sterols in human stenotic aortic valves

Contact Info

Product

Resources

About