Role of protein deimination in cardiovascular diseases: potential new avenues for diagnostic and prognostic biomarkers

Figures & data

Table 1. Reported PADs isoforms, citrullinated proteins and mechanisms, in cardiovascular experimental data sets

Conditions	Citrullinated proteins	Mechanism and PAD isoform involved	Example of Reference
Neutrophiles	Histone 3, NF-kB p65 subunit	NETosis driven by PAD2 NETosis driven by PAD4	Vejlstrup et al. [76], Du et al. [67], Knight et al. [40]
Macrophages	Vimentin, Histone 3, PAI-2	Not studied – possible METosis-PAD2 METsis-PAD2 and PAD4 NETosis driven by PAD4	Lai et al. [84], Yu et al. [85], Mishra et al. [86], Knight et al. [40]
Cardiomyocytes	Myosin Heavy Chain, Tropomyosin	Not studied	Giles et al [90], Fert-Bober et al [91]
Fibroblast	Fibronectin, Vimentin, ACPAs	Not studied – possible METosis-PAD2 Not studied Not studied	Li et al. [94], Shelef et al. [92], Sun et al. [93]
Clinical Vascular Dysfunction
Ischemia/reperfusion	Histone 3	NETosis-PAD4	Savchenko et al. [57], Bonaventura et al [75], Du et al. [67], Helseth et al. [77,78]
Atherosclerosis	Histone 3, NF-kB, H4R3	NETosis driven by PAD4	Knight et al [40], Sokolove et al. [152], Cambridge et al. [156]
Fibrosis/aging	Histone 3	NETosis driven by PAD4	Giles et al. [90], Martinod et al. [41]
Thrombosis	ADAMTS13, Antithrombin, Antiplasmin, PAI1	in vitro study direct citrullination NETosis-PAD4	Damiana et al. [70], De Meyer [71], Fuchs et al. [141], Sipilä et al. [28]
Cardiovascular heart diseases (CHD)	Vimentin, Fibrinogen, ACPA	NETosis-PAD4	Ling et al. [74], Geraldino-Pardilla et al. [153], Hermans et al. [155], Cambridge et al. [156]

Figure 1. Overview of the citrullinated proteins in the cardiovascular system. PAD mediated deimination in the field of cardiovascular diseases has been extensively studied in the last decade. It is suggested that citrullinated proteins play a critical role in the acute and the chronic inflammatory process that impair cardiovascular structure and function.

Figure 2. PADs activity interweaves atherosclerosis and thrombosis. NETs with H3Cit and PAD4 are involved in the whole process of atherosclerosis. PAD4 from NETs can stimulate macrophages to oxidize LDL to ox-LDL and turn into foam cells. Hyperlipidemia recruits’ neutrophils in the bone marrow into the circulation by upregulating the expression of granulocyte colony-stimulating factor and downregulating the level of C-X-C motif ligand −12, an important signal for the clearance and recruitment of aged neutrophils to the bone marrow. The macrophages activated by PAD4 driven NETosis undergo METosis. METosis increased pro-inflammatory cytokine production, including IL-1B. IL-1B activates Th17 cells to release IL-17, amplifying the immune cell recruitment to atherosclerotic plaques. NETs promote the expression of VWF and P-selectin on the surface of venous endothelia to entrap platelets and erythrocytes, thereby creating a scaffold for fibrin deposition. Meanwhile, cit-ADAMST13 dramatically inhibits its own activity and reduces the clearance of VWF-platelet strings, thereby accelerating thrombosis.

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