Overexpression of Catalase in Vascular Smooth Muscle Cells Prevents the Formation of Abdominal Aortic Aneurysms

Abstract

Objective Elevated levels of oxidative stress have been reported in abdominal aortic aneurysms (AAA), but which reactive oxygen species (ROS) promotes the development of AAA remains unclear. Here we investigate the effect of the hydrogen peroxide (H2O2) degrading enzyme catalase on the formation of AAA. Approach and Results AAA were induced with the application of calcium chloride (CaCl2) on mouse infrarenal aortas. The administration of PEG-catalase, but not saline, attenuated the loss of tunica media and protected against AAA formation (0.91±0.1 mm vs. 0.76±0.09 mm). Similarly, in a transgenic mouse model, catalase over-expression in the vascular smooth muscle cells (VSMC) preserved the thickness of tunica media and inhibited aortic dilatation by 50% (0.85±0.14 mm vs. 0.57±0.08 mm). Further studies showed that injury with CaCl2 decreased catalase expression and activity in the aortic wall. Pharmacologic administration or genetic over-expression of catalase restored catalase activity and subsequently decreased matrix metalloproteinase activity. In addition, a profound reduction in inflammatory markers and VSMC apoptosis was evident in aortas of catalase over-expressing mice. Interestingly, as opposed to infusion of PEG-catalase, chronic over-expression of catalase in VSMC did not alter the total aortic H2O2 levels. Conclusions The data suggest that a reduction in aortic wall catalase activity can predispose to AAA formation. Restoration of catalase activity in the vascular wall enhances aortic VSMC survival and prevents AAA formation primarily through modulation of matrix metalloproteinase activity.

Aortic Iron Overload With Oxidative Stress and Inflammation in Human and Murine Abdominal Aortic Aneurysm

“…In addition, previous studies have reported that antioxidant subjects inhibit AAA formation via attenuation of MMP activity in murine AAA models. [19][20][21] Therefore, oxidative stress is considered to be one of the therapeutic targets for AAA. However, it is well known that iron is a powerful mediator of oxidative stress.…”

Intermedin 1− 53 Attenuates Abdominal Aortic Aneurysm by Inhibiting Oxidative Stress

“…IMD decreased the protein expression of the proapoptotic proteins bax and p53 but upregulated the antiapoptotic protein bcl2. Previous studies have shown that blocking VSMC apoptosis with the antioxidant vitamin C 41 or overexpressing catalase 35 protected mice against aneurysm expansion. Consistent with these studies, our in vitro data demonstrated that IMD and antioxidant NAC both attenuated the VSMC apoptosis induced by Ang II.…”

“…Previous studies have reported that IMD could ameliorate vascular and renal injury by inhibiting oxidative stress 20 and showed antioxidant effects on myocardial injury, 21 which strongly supports the antioxidant effect of IMD in this study. In light of the evidence that antioxidants such as vitamin E 33 , quercetin, 34 or overexpression of catalase 35 could prevent experimental AAA formation, IMD may prevent AAA via its antioxidant effect, which may explain, in part, the inhibition of MMP activity by IMD.…”

“…8,26 We found that IMD and antioxidant NAC both decreased the protein expression of IL-6, MCP-1, nuclear factor-κB, and tumor necrosis factor-α in adventitial fibroblasts, where proinflammatory cytokines are mainly observed in AAA according to our present and previous study. 8,22 Pharmacological inhibition of oxidative stress has been reported to attenuate inflammation in AAA, 32,33,35 so the anti-inflammatory effect of IMD, at least in part, is mediated by inhibiting oxidative stress.…”

Vascular Function

“…However, it remains to be elucidated which ROS promotes the development of vascular disease. A recent article in ATVB by Parastatidis et al 12 examined the effect of hydrogen peroxide (H 2 O 2 )-degrading enzyme catalase on the formation of aortic aneurysms. They showed that restoration of catalase activity in the vascular wall enhances aortic VSMC survival and prevents aneurysm formation primarily through modulation of MMP activity.…”