Peptide Inhibitor of CXCL4–CCL5 Heterodimer Formation, MKEY, Inhibits Experimental Aortic Aneurysm Initiation and Progression

Abstract

Objective Macrophages are critical contributors in abdominal aortic aneurysm (AAA) disease. We examined the ability of MKEY, a peptide inhibitor of CXCL4-CCL5 interaction, to influence AAA progression in murine models. Methods and Results AAAs were created in 10-week-old male C57BL/6 mice by transient infrarenal aortic porcine pancreatic elastase (PPE) infusion. Mice were treated with MKEY via intravenous injection either 1) before PPE infusion, or 2) after aneurysm initiation. Immunostaining demonstrated CCL5 and CCR5 expression on aneurysmal aortae and mural monocytes/macrophages, respectively. MKEY treatment partially inhibited transmural AAA migration of adaptively transferred leukocytes in recipient mice. While all vehicle-pretreated mice developed AAA, aneurysms formed in only 60% (3/5) and 14% (1/7) of mice pretreated with MKEY at 10 and 20 mg /kg, respectively. MKEY pretreatment reduced aortic diameter enlargement, preserved medial elastin fibers and smooth muscle cells, and attenuated mural macrophage infiltration, angiogenesis, and aortic MMP2 & 9 expression following PPE infusion. MKEY initiated after PPE infusion also stabilized and/or reduced enlargement of existing AAAs. Finally, MKEY treatment was effective in limiting AAA formation following angiotensin II infusion in apolipoprotein E deficient mice. Conclusion MKEY suppresses AAA formation and progression in two complementary experimental models. Peptide inhibition of CXCL4-CCL5 interactions may represent a viable translational strategy to limit progression of human AAA disease.

Activation of endocannabinoid system is associated with persistent inflammation in human aortic aneurysm

“…Still, we found a significantly lower expression of potent chemotactic mediator chemokine CCL2, which may reflect a negative feedback regulation of leukocyte infiltration in order to keep the inflammation at a very low level. This finding is very interesting since experimental studies have suggested beneficial effects of chemokine inhibition on formation of aneurysms [8], but future studies specifically targeting chemokines should clarify their contribution to this pathology. Another interesting aspect regarding production of reactive oxygen species has also been associated with human aortic aneurysms [10].…”

“…A combination of causes is assumed in patients with bicuspid aortic valve, which have a higher risk of aortic dilation or dissection, probably due to altered regional hemodynamics and structural anatomy of the aortic wall [5,6]. Inflammation has also been suggested in the development of abdominal aortic aneurysms, since cellular infiltration via vasa vasorum was observed in the aortic wall and associated with expression of inflammatory mediators [7,8]. Because of differences in aetiologies [9], these findings from abdominal aneurysms cannot be directly projected into thoracic aneurysms, where we lack an evidence for inflammation.…”

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

“…Additional inflammatory pathways are also involved in the action of Ang II. Some evidence has suggested that CCL5 also has an important role in Ang II induced dissecting AAA [41]. Moreover, Ang II may stimulate the expression of cyclooxygenase-2 (COX-2) [42,43], a critical enzyme in AAA pathogenesis that forms vasoactive and inflammatory prostaglandins.…”

Role of Platelet-Mediated Cytoadherence and Chemokines Release in Severe Malaria

“…Moreover, the heteromeric form of CXCL4 may also bind to receptors other than CXCR3, for the activation of T-cells. Blocking these heteromerization may require further studies and can be a valuable therapeutic target as it has been shown in the case of aortic aneurysm [26].…”