Disease-associated increased HIF-1, αvβ3 integrin, and Flt-1 do not suffice to compensate the damage-inducing loss of blood vessels in inflammatory myopathies

Konttinen, Yrjö T.; Mackiewicz, Z; Povilenaite, D; Sukura, Antti; Hukkanen, Mika; Virtanen, Ismo

doi:10.1007/s00296-003-0379-z

Cited by 22 publications

(12 citation statements)

References 34 publications

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“…The HIF1α-deficient macrophages and neutrophils had reduced levels of cellular ATP (15–40% of wild-type levels), highlighting the crucial role of the transcription factor for energy generation through glycolysis in these immune cells 15 . Evidence of HIF activation in the diseased tissues of patients with inflammatory disorders such as rheumatoid arthritis 16, 17 , dermatomyositis 18 , congenital lupus 19 and atherosclerosis 20 , corroborates an important role for the hypoxic response in various human immunopathologies.…”

Section: Hif Function In Myeloid Cellsmentioning

confidence: 80%

Interdependence of hypoxic and innate immune responses

Nizet

Johnson²

2009

Nat Rev Immunol

629

600

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Hypoxia-inducible transcription factor (HIF) is a major regulator of cellular metabolism and adaptation to cellular stress caused by oxygen deficiency (hypoxia). Phagocytic cells have an essential role in innate immune defense against pathogens; and this is a battle that takes place mainly in the hypoxic microenvironments of infected tissues. It has now become clear that HIF promotes the bactericidal activities of phagocytic cells and supports the innate immune functions of dendritic cells, mast cells and epithelial cells. In response to microbial pathogens, HIF expression is upregulated through pathways involving the key immune response regulator nuclear factor-κB, highlighting an interdependence of the innate immune and hypoxic responses to infection and tissue damage. In turn, HIF-driven innate immune responses have important consequences for both the pathogen and the host, and its central role in immune defence demonstrates the importance of the tissue microenvironment in controlling infectious disease.

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Section: Hif Function In Myeloid Cellsmentioning

confidence: 80%

Interdependence of hypoxic and innate immune responses

Nizet

Johnson²

2009

Nat Rev Immunol

629

600

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“…To what extent these mechanisms contribute to muscle weakness in IIM remains to be elucidated, although clearly ROS plays an important generic role in mediating muscle function and dysfunction in myopathologies other than IIM 10 52. Alternate non-immune mechanisms of weakness such as hypoxia have been described in the context of IIM, with patients with myositis having a lower muscle capillary density 53 54. Moreover, the relationship between hypoxia and modified ROS generation has received significant attention.…”

Section: Ros As Mediators Of Skeletal Muscle Weaknessmentioning

confidence: 99%

In the idiopathic inflammatory myopathies (IIM), do reactive oxygen species (ROS) contribute to muscle weakness?

et al. 2015

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The idiopathic inflammatory myopathies (IIMs) are a group of rare autoimmune disorders, collectively known as myositis. Affected patients present with proximal muscle weakness, which usually improves following treatment with immunosuppressants, but often incompletely so, thus many patients remain weak. IIMs are characterised histologically by inflammatory cell infiltrates into skeletal muscle and overexpression of major histocompatibility complex I on muscle cell surfaces. Although inflammatory cell infiltrates represent a major feature of myositis there is growing evidence that muscle weakness correlates only poorly with the degree of cellular infiltration, while weakness may in fact precede such infiltrations. The mechanisms underpinning such non-immune cell mediated weakness in IIM are poorly understood. Activation of the endoplasmic reticulum stress pathways appears to be a potential contributor. Data from non-muscle cells indicate that endoplasmic reticulum stress results in altered redox homeostasis capable of causing oxidative damage. In myopathological situations other than IIM, as seen in ageing and sepsis, evidence supports an important role for reactive oxygen species (ROS). Modified ROS generation is associated with mitochondrial dysfunction, depressed force generation and activation of muscle catabolic and autophagy pathways. Despite the growing evidence demonstrating a key role for ROS in skeletal muscle dysfunction in myopathologies other than IIM, no research has yet investigated the role of modified generation of ROS in inducing the weakness characteristic of IIM. This article reviews current knowledge regarding muscle weakness in the absence of immune cells in IIM, and provides a background to the potential role of modified ROS generation as a mechanism of muscle dysfunction. The authors suggest that ROS-mediated mechanisms are potentially involved in non-immune cell mediated weakness seen in IIM and outline how these mechanisms might be investigated in this context. This appears a timely strategy, given recent developments in targeted therapies which specifically modify ROS generation.

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“…31,32 DM is characterized by perifascicular atrophy, perivascular inflammation, microvascular deposits of the C5b-9 membrane attack complex on endothelial cells, and endomysial capillaries that are enlarged and reduced in number, with partial endothelial swelling. [31][32][33] Thus, the ACE polymorphism could additionally contribute to the microvascular pathology findings in DM. Furthermore, we have recently observed a high prevalence of metabolic syndrome and CVD parameters, such as stroke and defined-diabetes mellitus, in patients with DM.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-converting enzyme insertion/deletion gene polymorphism is associated with dermatomyositis

Shinjo

Uno

Oba-Shinjo

et al. 2014

J Renin Angiotensin Aldosterone Syst

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Background and objective: The cornerstone of dermatomyositis (DM) pathogenesis involves vascular disturbance that leads to hypoxia, capillary necrosis and muscle perifascicular atrophy. Hence, the hypothesis is that the angiotensinconverting enzyme (ACE) insertion/deletion (I/D) gene polymorphism could be associated with susceptibility to DM. Method: A single centre, case control study that genotyped ACE gene in 88 DM and 99 healthy individuals. The ACE gene polymorphism was determined by melting curve analysis of real-time polymerase chain reaction products using SYBR Green. Results: The DM and the control subjects had a comparable mean age, gender frequency and ethnicity. The frequency of the D allele was higher in DM than in the control individuals (63.6% vs 55.6%, respectively). The DM had more ACE D/D and less ACE I/D genotype when compared to the control individuals, whereas the ACE I/I genotype distribution was similar in both case and control groups. Moreover, after sex-age-adjusted analysis, the ACE D/D genotype was strongly associated with DM disease (odds ratio (OR) 2.44, 95% confidence interval (CI): 1.17-4.37), in contrast to ACE I/D genotype (OR 0.51, 95% CI: 0.28-0.93). Conclusions: Homozygous ACE D/D was associated significantly with the DM risk. Further investigations are required to clarify and to confirm the association of these genes with DM susceptibility.

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Disease-associated increased HIF-1, αvβ3 integrin, and Flt-1 do not suffice to compensate the damage-inducing loss of blood vessels in inflammatory myopathies

Cited by 22 publications

References 34 publications

Interdependence of hypoxic and innate immune responses

Interdependence of hypoxic and innate immune responses

In the idiopathic inflammatory myopathies (IIM), do reactive oxygen species (ROS) contribute to muscle weakness?

Angiotensin-converting enzyme insertion/deletion gene polymorphism is associated with dermatomyositis

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