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Complement C3: an emerging risk factor in cardiometabolic disease.

Hertle E, van Greevenbroek MM, Stehouwer CD - Diabetologia (2012)

Bottom Line: C3 is the central component of the complement system and activation of C3 via any of the three major activation pathways-the classical, the lectin and the alternative pathways-results in initiation of the terminal complement pathway and release of the anaphylatoxin C3a.Recent data suggest a diabetes-dependent incorporation of C3 into fibrin clots, with concomitant effects on clot characteristics.Taken together, epidemiological and experimental evidence concordantly point to a role of complement C3 in metabolic, atherosclerotic/atherothrombotic and microangiopathic processes and further research should be directed towards the elucidation of complement function and activation in cardiometabolic disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.

ABSTRACT
C3 is the central component of the complement system and activation of C3 via any of the three major activation pathways-the classical, the lectin and the alternative pathways-results in initiation of the terminal complement pathway and release of the anaphylatoxin C3a. Both terminal pathway activation and signalling of C3a and its inactivation product C3a-desarg via the C3a receptor and C5a-like receptor 2, respectively, can induce inflammatory, immunomodulatory and metabolic responses. C3 has been implicated in metabolic disorders, notably adiposity, dyslipidaemia, insulin resistance, liver dysfunction and diabetes, and C3 is increasingly recognised as a cardiometabolic risk factor. C3 may play a role in the macrovascular, as well as microvascular, complications of diabetes. Moreover, C3 may interact with the coagulation system and as such also contribute to a procoagulant, hypofibrinolytic and, ultimately, prothrombotic state. Recent data suggest a diabetes-dependent incorporation of C3 into fibrin clots, with concomitant effects on clot characteristics. Taken together, epidemiological and experimental evidence concordantly point to a role of complement C3 in metabolic, atherosclerotic/atherothrombotic and microangiopathic processes and further research should be directed towards the elucidation of complement function and activation in cardiometabolic disorders.

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Related in: MedlinePlus

Adiposity, inflammation, immune activation, insulin resistance, hypertriglyceridaemia and, potentially, hyperglycaemia may lead to increased systemic levels of C3. C3a and C3b are generated upon activation of C3. C3b is part of the multi-step complement activation cascade that eventually leads to the formation of soluble (s) TCCs/MACs. The anaphylatoxin C3a is rapidly degraded into its desarginated form, which is also known as ASP. Both C3a and C3a-desarg/ASP can, via binding to their respective receptors (C3aR and C5L2), exert relevant effects with respect to diabetes and CVD. The solid arrows denote direct effects, the dotted arrows denote more distal effects and the lightening bolts indicate activation
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Fig1: Adiposity, inflammation, immune activation, insulin resistance, hypertriglyceridaemia and, potentially, hyperglycaemia may lead to increased systemic levels of C3. C3a and C3b are generated upon activation of C3. C3b is part of the multi-step complement activation cascade that eventually leads to the formation of soluble (s) TCCs/MACs. The anaphylatoxin C3a is rapidly degraded into its desarginated form, which is also known as ASP. Both C3a and C3a-desarg/ASP can, via binding to their respective receptors (C3aR and C5L2), exert relevant effects with respect to diabetes and CVD. The solid arrows denote direct effects, the dotted arrows denote more distal effects and the lightening bolts indicate activation

Mentions: C3 lies at the heart of the complement network, as all three major activation pathways may result in cleavage of C3 and initiation of the downstream terminal pathway. Systemic levels of C3 may reflect the potential for complement activation. Upon activation of C3, C3a and C3b are generated. Once formed, the anaphylatoxin C3a is rapidly desarginated by a carboxypeptidase, generating C3a-desarg. Although this was previously thought to be an inactivation process, C3a-desarg has been recognised as a lipogenic hormone and is now also known as acylation-stimulating protein (ASP) [1]. C3b is instrumental in the activation of the terminal pathway of complement activation, which leads to formation of TCCs/MACs (Fig. 1).Fig. 1


Complement C3: an emerging risk factor in cardiometabolic disease.

Hertle E, van Greevenbroek MM, Stehouwer CD - Diabetologia (2012)

Adiposity, inflammation, immune activation, insulin resistance, hypertriglyceridaemia and, potentially, hyperglycaemia may lead to increased systemic levels of C3. C3a and C3b are generated upon activation of C3. C3b is part of the multi-step complement activation cascade that eventually leads to the formation of soluble (s) TCCs/MACs. The anaphylatoxin C3a is rapidly degraded into its desarginated form, which is also known as ASP. Both C3a and C3a-desarg/ASP can, via binding to their respective receptors (C3aR and C5L2), exert relevant effects with respect to diabetes and CVD. The solid arrows denote direct effects, the dotted arrows denote more distal effects and the lightening bolts indicate activation
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3295998&req=5

Fig1: Adiposity, inflammation, immune activation, insulin resistance, hypertriglyceridaemia and, potentially, hyperglycaemia may lead to increased systemic levels of C3. C3a and C3b are generated upon activation of C3. C3b is part of the multi-step complement activation cascade that eventually leads to the formation of soluble (s) TCCs/MACs. The anaphylatoxin C3a is rapidly degraded into its desarginated form, which is also known as ASP. Both C3a and C3a-desarg/ASP can, via binding to their respective receptors (C3aR and C5L2), exert relevant effects with respect to diabetes and CVD. The solid arrows denote direct effects, the dotted arrows denote more distal effects and the lightening bolts indicate activation
Mentions: C3 lies at the heart of the complement network, as all three major activation pathways may result in cleavage of C3 and initiation of the downstream terminal pathway. Systemic levels of C3 may reflect the potential for complement activation. Upon activation of C3, C3a and C3b are generated. Once formed, the anaphylatoxin C3a is rapidly desarginated by a carboxypeptidase, generating C3a-desarg. Although this was previously thought to be an inactivation process, C3a-desarg has been recognised as a lipogenic hormone and is now also known as acylation-stimulating protein (ASP) [1]. C3b is instrumental in the activation of the terminal pathway of complement activation, which leads to formation of TCCs/MACs (Fig. 1).Fig. 1

Bottom Line: C3 is the central component of the complement system and activation of C3 via any of the three major activation pathways-the classical, the lectin and the alternative pathways-results in initiation of the terminal complement pathway and release of the anaphylatoxin C3a.Recent data suggest a diabetes-dependent incorporation of C3 into fibrin clots, with concomitant effects on clot characteristics.Taken together, epidemiological and experimental evidence concordantly point to a role of complement C3 in metabolic, atherosclerotic/atherothrombotic and microangiopathic processes and further research should be directed towards the elucidation of complement function and activation in cardiometabolic disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.

ABSTRACT
C3 is the central component of the complement system and activation of C3 via any of the three major activation pathways-the classical, the lectin and the alternative pathways-results in initiation of the terminal complement pathway and release of the anaphylatoxin C3a. Both terminal pathway activation and signalling of C3a and its inactivation product C3a-desarg via the C3a receptor and C5a-like receptor 2, respectively, can induce inflammatory, immunomodulatory and metabolic responses. C3 has been implicated in metabolic disorders, notably adiposity, dyslipidaemia, insulin resistance, liver dysfunction and diabetes, and C3 is increasingly recognised as a cardiometabolic risk factor. C3 may play a role in the macrovascular, as well as microvascular, complications of diabetes. Moreover, C3 may interact with the coagulation system and as such also contribute to a procoagulant, hypofibrinolytic and, ultimately, prothrombotic state. Recent data suggest a diabetes-dependent incorporation of C3 into fibrin clots, with concomitant effects on clot characteristics. Taken together, epidemiological and experimental evidence concordantly point to a role of complement C3 in metabolic, atherosclerotic/atherothrombotic and microangiopathic processes and further research should be directed towards the elucidation of complement function and activation in cardiometabolic disorders.

Show MeSH
Related in: MedlinePlus