Aneurysm formation and bradykinin

Abstract

In this issue, Merino et al. publish a provocative paper on accelerated aortic aneurysm formation in mice lacking both apolipoprotein E (APOE) and the bradykinin[1] (B1) receptor [1]. Their disease model is the APOE genedeleted (−/−) mouse that I admittedly love. These are indeed the mice that "keep on giving" [2]. APOE−/− mice not only are cooperative in terms of developing atherosclerosis but also develop aortic aneurysms when infused with angiotensin (Ang) II, making them an ideal model for studying this serious clinical disease [3]. APOE−/− mice are not unique in this regard; low-density lipoprotein receptor −/− mice work equally as well. The role of Ang II is interesting and is independent of the blood pressure increase [4]. Norepinephrine, on the other hand, is much less prone to provoke aneurysm formation.Merino et al.[1] fed APOE gene-deficient mice and APOE-deficient mice that had been crossed into a B1 receptor −/− model namely, an APOE−/− and B1−/− "double-knockout" model, a high-fat diet. The cholesterol elevations of both groups were the same. However, the absent B1 receptors made the atherosclerosis and aneurysm formation worse. The expressions of cyclic guanylyl monophosphate (cGMP)-dependent kinase I, CD-11, F4/ 80, monocyte colony-stimulating factor (mCSF), and tumor necrosis factor (TNF)-α were also increased in the aortas of the double knockout, compared to APOE−/− mice. Peroxisome proliferator-activated receptor γ (PPARγ) protein and the matrix metalloproteinase-9 (MMP9) activity, on the other hand, were decreased in the aortas of the doubleknockout mice. Remarkably, Ang II was not required for aneurysm formation, although Ang II infusion experiments in the mice were conducted. Again, aneurysm formation in the double-knockout mice was worse than in other groups.What is it about the bradykinin B1 receptor? The B1 receptor plays an important role in mediating the inflammatory effects of the kallikrein-kinin pathway. The B1 receptor −/− mice have revealed that the receptor plays a pivotal role in the cellular, particularly neutrophil, recruitment associated with acute inflammatory responses. Neutrophil recruitment has been implicated in the early stages of atherosclerosis. The B1 receptor plays a major role in chemokine (CXCL5 and CCL2) expression. Thus, we might have speculated that absence of the B1 receptor would protect from atherosclerosis and aneurysm formation, rather than the other way around. The authors argue that upregulation of cGMP-dependent kinase I could have facilitated the atherosclerosis. Indeed, a proatherosclerotic role for cGMP-dependent protein kinase I has been described in vascular smooth muscle cells [5]. The cGMP-dependent protein kinase I is a potential mediator of nitric oxide (NO) signaling in vascular smooth muscle cells. Postnatal ablation of cGMP-dependent protein kinase I selectively in the vascular smooth muscle cells of mice reduced atherosclerotic lesion area, demonstrating that smooth muscle cGMP-dependent protein kinase I promotes atherogenesis. Cell fate ma...