Cardiovascular Disease

Complement, as the traditional defense line of innate immunity, has a broad range of physiologic functions, including the opsonization of microbial pathogens with C1q or mannose-binding lectin (MBL), the induction of mast cell degranulation via soluble anaphylatoxins C3a and C5a, the attraction of inflammatory cells, the cytolysis mediated by the membrane attack complex (MAC).

Cardiovascular Disease

Beyond immune defense, the complement system directs the maintenance of tissue homeostasis and cellular integrity as well as in tissue regeneration. Moderate activation of the complement system has unassailable beneficial functions for our organism, but excessive activation of the system may lead to uncontrolled self-tissue damage and various diseases. Now considerable evidence suggests that the complement plays an important role in the pathophysiology of cardiovascular disease (CVD), including:

1. Subacute myocardial infarction
2. Acute ischemic stroke

CVD is a major clinical manifestation of cardiometabolic disorders, which is characterized by critically narrowing (stenosis) or occlusion (atherothrombosis) of blood vessels, including the heart and peripheral or cerebral vessels. The complement system is evaluated to partake in key processes of CVD, such as endothelial dysfunction, atherosclerosis, and impaired regulation of coagulation and fibrinolysis.

1. The complement system contributes to endothelial dysfunction. When suffering from endothelial dysfunction, the capacity for vasodilation is reduced, which impairs blood pressure regulation. Furthermore, dysfunctional endothelial cells express adhesion molecules that enhance adherence and migration of inflammatory cells, which initiate and promote atherosclerosis. C3a, C5a, and C5b-9 can induce the expression of adhesion molecules and proinflammatory cytokines in endothelial cells.
2. Complement participates in the process of atherosclerosis. Complement is activated in early fatty streaks and also in late stages of atherosclerosis (major plaque/atheroma). Complement components can be observed in the atheroma, and present colocalization with potential activators such as CRP, oxidized low-density lipoproteins (LDL), gC1qR and macrophages/foam cells. C1q, C1r, C1s, C4, C7, and C8 were also detected in human plaques. Moreover, mannose-binding lectin (MBL), one of the key factors of lectin pathways, is potentially relevant to the pathogenesis of coronary artery disease and myocardial infarction: inflammation, thrombosis, apoptosis, and so on. MBL may also have a significant impact on the formation and destabilization of the atherosclerotic plaque and thrombosis.
3. Complement contributes to CVD via its functions in coagulation and fibrinolysis. C3 was found to be associated with fibrinogen, platelet count and plasminogen activator inhibitor-1 (PAI-1). Recognized as a structural component of blood clots, plasma C3 concentration is correlated with the extent of C3 incorporation into fibrin clots.

Fig. 1 Vascular disease development through exosome-mediated paracrine signaling.^{1, 2}

The complement system plays a central, causative role in the pathogenesis of cardiovascular disease. So the complement components have the ability for genetic risk prediction and clinical trials of novel therapies.

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References

1. Jadli, Anshul S., et al. "Exosomes in cardiovascular diseases: pathological potential of nano-messenger." Frontiers in Cardiovascular Medicine 8 (2021): 767488.
2. under Open Access license CC BY 4.0, without modification.

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