The advantageous role of annexin A1 in cardiovascular disease

Figures & data

Figure 1. Annexin A1 (ANXA1) moderates leukocyte recruitment by instructing leukocytes and endothelial cells to prevent excessive leukocyte adhesion to the vascular wall. (1) ANXA1 interferes with chemokine induced Rap1 activation and consequently with integrin activation and clustering via FPR2. (2) HDL increases endogenous ANXA1 expression in TNF-α activated endothelial cells via SR-B1. Exogenous ANXA1 prohibits TNF-induced Rac1 activation and therefore superoxide production and cell adhesion molecule expression via binding FPR2. Reduced expression of adhesion molecules on the cell surface of endothelial cells limits leukocyte adhesion and recruitment. Abbreviations: FPR2, formyl peptide receptor 2; CCR/CXCR, CC-chemokine receptor/CXC-chemokine receptor; HDL, high density lipoprotein; apoA-1, apolipoprotein A1; SR-B1, scavenger receptor class B type 1; TNF-α, tumor necrosis factor α.

Table 1. Pharmacokinetics and therapeutic potential of Annexin A1 and its derived peptides in cardiovascular disease models.

Drug	Disease model	Administration	Pharmacokinetics	Outcome	Ref.
Atherosclerosis
Col IV–Ac2–26 NPs	Advanced atherosclerosis	NPs contain 10 μg of Ac2–26 per injection (mouse) 1x/week, 5 weeks (starting after 12 weeks HFD)	Linear release in 96 hours (in vitro)	Lesion size ↓ Plaque stability ↑ Oxidative stress ↓ Necrotic area ↓ ICAM-1↓ Lesional IL10 ↑	105
Ac2–26	Atherogenesis	50 μg/injection (mouse) 3x/week, 4 weeks	Not studied	Lesion size ↓ Leukocyte recruitment ↓ Integrin activation ↓	65
h-annexin A1	Atherogenesis Advanced atherosclerosis	1 mg/kg (mouse) 3x/week, 6 weeks 3x/week, 6 weeks (starting after 6 weeks HFD)	Peaks after 50 min in the blood circulation T½ = 6 hours	No effect Lesion size ↓ Necrotic core ↓	61
Myocardial infarction
Ac2–26	I/R	5 or 50 μg/injection (rat) At the start of reperfusion	Not studied	Infarct area ↓ Myocardial MPO ↓ Myocardial TNF-α ↓ Myocardial CCL3 ↓ Leukocyte adhesion ↓	113
Ac2–26 h-annexin A1	I/R	0.5 or 1 mg/kg (rat) 0, 30 and 60 min after reperfusion 25 mg/kg (rat)	Not studied	Infarct area ↓ Myocardial MPO ↓ Myocardial IL-1β ↓ Infarct area ↓	111
Ac2–26	I/R	1 mg/kg (mouse) At the start of reperfusion	Not studied	Infarct area ↓ Neutrophil count ↓ Myocardial CXCL1 ↓	112
AnxA12–50 or CR-AnxA12–50	I/R	5 μg/injection (mouse) 0 and 60 min after reperfusion	Not studied	Infarct size ↓ Plasma troponin levels ↓ Plasma CCL5 levels ↓ Plasma IL1β levels ↓ Incidence of death (after 24 hr) ↓	74
Stroke
Annexin A1 fragment (NH2-terminal 1–188 aa)	I/R	1.2 μg/injection (rat) 10 min after start ischemia	Not studied	Infarct size ↓ Cerebral edema ↓	118
h-annexin A1 Ac2–26	I/R	1 μg/injection (mouse) Repetitive injection after 0, 6 and 18 hours 100 μg/injection (mouse) (Repetitive) injection after 0, 6 and/or 18 hours	Not studied	Infarct volume ↓ Neurological score ↓ Leukocyte adhesion ↓ MPO activity ↓ Infarct volume (best results obtained with an injection after 1 and 18 hours) ↓ Neurological score ↓ Leukocyte adhesion ↓	119
Ac2–26	I/R	2.5 μg/kg (mouse) At the start of the reperfusion	Not studied	Leukocyte adhesion ↓	75
Ac2–26	I/R	100 μg/injection (mouse) At the start of cerebral reperfusion	Not studied	Infarct volume ↓ Neurological score ↓ Neutrophil-platelet aggregation ↓ Leukocyte adherence ↓ Platelet adherence ↓	72

Abbreviations: Col, collagen; NPs, nanoparticles; HFD, high fat diet; IL, interleukin; ICAM-1, intracellular adhesion molecule-1; Ac2–26, N-terminal fragment of Annexin A1; h-, human-; I/R, ischemia/reperfusion; CCL, CC chemokine ligand; CXCL, CXC chemokine ligand; CR-AnxA12–50, cleavage resistant annexin A1_2–50; MPO, Myeloperoxidase.