Satoh, K. et al. Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms. Nat. Med. 15, 649-656

Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Nature medicine (Impact Factor: 27.36). 06/2009; 15(6):649-56. DOI: 10.1038/nm.1958
Source: PubMed


Inflammation and oxidative stress are pathogenic mediators of many diseases, but molecules that could be therapeutic targets remain elusive. Inflammation and matrix degradation in the vasculature are crucial for abdominal aortic aneurysm (AAA) formation. Cyclophilin A (CypA, encoded by Ppia) is highly expressed in vascular smooth muscle cells (VSMCs), is secreted in response to reactive oxygen species (ROS) and promotes inflammation. Using the angiotensin II (AngII)-induced AAA model in Apoe-/- mice, we show that Apoe-/-Ppia-/- mice are completely protected from AngII-induced AAA formation, in contrast to Apoe-/-Ppia+/+ mice. Apoe-/-Ppia-/- mice show decreased inflammatory cytokine expression, elastic lamina degradation and aortic expansion. These features were not altered by reconstitution of bone marrow cells from Ppia+/+ mice. Mechanistic studies showed that VSMC-derived intracellular and extracellular CypA are required for ROS generation and matrix metalloproteinase-2 activation. These data define a previously undescribed role for CypA in AAA formation and suggest CypA as a new target for treating cardiovascular disease.

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    • "In the current study, we examined whether the preventive effect of FA extends to other models of AAA. We chose to use the Ang II infused apoE null model of AAA, as it is a well-characterized murine model for AAA [7], [19], [20] that is different from our previous model of hph-1 mice. The results show that oral treatment of FA significantly reduced the incidence of AAA from 92% to 19.5%. "
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    ABSTRACT: We have previously shown that eNOS uncoupling mediates abdominal aortic aneurysm (AAA) formation in hph-1 mice. In the present study we examined whether recoupling of eNOS prevents AAA formation in a well-established model of Angiotensin II-infused apolipoprotein E (apoE) null mice by targeting some common pathologies of AAA. Infusion of Ang II resulted in a 92% incidence rate of AAA in the apoE null animals. In a separate group, animals were treated orally with folic acid (FA), which is known to recouple eNOS through augmentation of dihydrofolate reductase (DHFR) function. This resulted in a reduction of AAA rate to 19.5%. Imaging with ultrasound showed that FA markedly inhibited expansion of abdominal aorta. FA also abolished elastin breakdown and macrophage infiltration in the AAA animals. The eNOS uncoupling activity, assessed by L-NAME-sensitive superoxide production, was minimal at baseline but greatly exaggerated with Ang II infusion, which was completely attenuated by FA. This was accompanied by markedly improved tetrahydrobiopterin and nitric oxide bioavailability. Furthermore, the expression and activity of DHFR was decreased in Ang II-infused apoE null mice specifically in the endothelial cells, while FA administration resulted in its recovery. Taken together, these data further establish a significant role of uncoupled eNOS in mediating AAA formation, and a universal efficacy of FA in preventing AAA formation via restoration of DHFR to restore eNOS function.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "The pathobiology of AAA embodies extracellular matrix degeneration and inflammation as its two major arms, which implicate a complex interplay of key mechanisms that include oxidative stress [13]–[15], local production of proinflammatory cytokines [16]–[17], vascular smooth muscle migration and proliferation [18]–[20], and activation of the three major protease families: matrix metalloproteinases, cysteine, and serine proteases [21]–[26]. Cumulative evidence indicates that the presence and action of smooth muscle cells is essential for Ang II-induced AAA formation and progression [15], [26]–[27]. Similarly, convergent lines of experimental and pathological evidence implicate early involvement of the monocyte/macrophage innate immune response, with consequent production of various proinflammatory cytokines during AAA development [22], [28]–[30]. "
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    ABSTRACT: Understanding variations in size and pattern of development of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) may inform translational research strategies. Thus, we sought insight into the temporal evolution of AAA in apolipoprotein (apo)E(-/-) mice. A cohort of mice underwent a 4-week pump-mediated infusion of saline (n = 23) or 1500 ng/kg/min of Ang II (n = 85) and AAA development was tracked via in vivo ultrasound imaging. We adjusted for hemodynamic covariates in the regression models for AAA occurrence in relation to time. The overall effect of time was statistically significant (p<0.001). Compared to day 7 of AngII infusion, there was no decrease in the log odds of AAA occurrence by day 14 (-0.234, p = 0.65), but compared to day 21 and 28, the log odds decreased by 9.07 (p<0.001) and 2.35 (p = 0.04), respectively. Hemodynamic parameters were not predictive of change in aortic diameter (Δ) (SBP, p = 0.66; DBP, p = 0.66). Mean total cholesterol (TC) was higher among mice with large versus small AAA (601 vs. 422 mg/ml, p<0.0001), and the difference was due to LDL. AngII exposure was associated with 0.43 mm (95% CI, 0.27 to 0.61, p<0.0001) increase in aortic diameter; and a 100 mg/dl increase in mean final cholesterol level was associated with a 12% (95% CI, 5.68 to 18.23, p<0.0001) increase in aortic diameter. Baseline cholesterol was not associated with change in aortic diameter (p = 0.86). These are the first formal estimates of a consistent pattern of Ang II-induced AAA development. The odds of AAA occurrence diminish after the second week of Ang II infusion, and TC is independently associated with AAA size.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "Indeed, the Rho-kinase/CyPA pathway plays a crucial role for AAA formation by promoting inflammation and MMP activation in a mouse AAA model [15]. We have recently demonstrated that Rho-kinase inhibitor Y27632 considerably reduces CyPA secretion from vascular smooth muscle cells and that CyPA is crucial for secretion and activation of MMPs using the ApoE-/-Ppia-/-double knockout mice [15]. In the present study, the location of AngII-induced CyPA expression was mostly VSMCs which highly coincide with that of Rho-kinase (Figure 7). "
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    ABSTRACT: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease. It is controversial whether statin and calcium channel blockers (CCBs) has an inhibitory effect on the expansion of AAA. Some studies reported that CCBs have an inhibitory effect on Rho-kinase activity. Rho-kinase plays an important role in the pathogenesis of various cardiovascular diseases. However, there is no study reporting of the association between Rho-kinase and human AAAs. Experimental AAA was induced in Apolipoprotein E-deficient (ApoE(-/-)) mice infused with angiotensin II (AngII) for 28 days. They were randomly divided into the following 5 groups; saline infusion alone (sham), AngII infusion alone, AngII infusion plus atorvastatin (10 mg/kg/day), AngII infusion plus amlodipine (1 mg/kg/day), and AngII infusion plus combination therapy with atorvastatin (10 mg/kg/day) and amlodipine (1 mg/kg/day). The combination therapy significantly suppressed AngII-induced increase in maximal aortic diameter as compared with sham, whereas each monotherapy had no inhibitory effects. The combination therapy significantly reduced AngII-induced apoptosis and elastin degradation at the AAA lesion, whereas each monotherapy did not. Moreover, Rho-kinase activity, as evaluated by the extent of phosphorylation of myosin-binding subunit (a substrate of Rho-kinase) and matrix metalloproteinase activity were significantly increased in the AngII-induced AAA lesion as compared with sham, both of which were again significantly suppressed by the combination therapy. In human aortic samples, immunohistochemistory revealed that the activity and expression of Rho-kinase was up-regulated in AAA lesion as compared with abdominal aorta from control subjects. Rho-kinase is up-regulated in the aortic wall of human AAA. The combination therapy with amlodipine and Atorvastatin, but not each monotherapy, suppresses AngII-induced AAA formation in mice in vivo, for which Rho-kinase inhibition may be involved.
    Preview · Article · Aug 2013 · PLoS ONE
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