Article

Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms.

Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Nature medicine (Impact Factor: 28.05). 06/2009; 15(6):649-56. DOI: 10.1038/nm.1958
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
281 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hard and soft structural composites found in biology provide inspiration for the design of advanced synthetic materials. Many examples of bio-inspired hard materials can be found in the literature; far less attention has been devoted to soft systems. Here we introduce deterministic routes to low-modulus thin film materials with stress/strain responses that can be tailored precisely to match the non-linear properties of biological tissues, with application opportunities that range from soft biomedical devices to constructs for tissue engineering. The approach combines a low-modulus matrix with an open, stretchable network as a structural reinforcement that can yield classes of composites with a wide range of desired mechanical responses, including anisotropic, spatially heterogeneous, hierarchical and self-similar designs. Demonstrative application examples in thin, skin-mounted electrophysiological sensors with mechanics precisely matched to the human epidermis and in soft, hydrogel-based vehicles for triggered drug release suggest their broad potential uses in biomedical devices.
    Nature Communications 03/2015; 6:6566. DOI:10.1038/ncomms7566 · 10.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims In this work we provide novel insight into the morphology of dissecting abdominal aortic aneurysms in angiotensin II-infused mice. We demonstrate why they exhibit a large variation in shape and, unlike their human counterparts, are located suprarenally rather than infrarenally. Methods and Results We combined synchrotron-based ultra-high resolution ex vivo imaging (phase contrast X-Ray tomographic microscopy) with in vivo imaging (high-frequency ultrasound and contrast-enhanced micro-CT) and image-guided histology. In all mice we observed a tear in the tunica media of the abdominal aorta near the ostium of the celiac artery. Independently we found that, unlike the gradual luminal expansion typical for human aneurysms, the outer diameter increase of angiotensin II-induced dissecting aneurysms in mice was related to one or several intramural hematomas. These were caused by ruptures of the tunica media near the ostium of small suprarenal side branches, which had never been detected by the established small-animal imaging techniques. The tear near the celiac artery led to apparent luminal dilatation, while the intramural hematoma led to a dissection of the tunica adventitia on the left suprarenal side of the aorta. The number of ruptured branches was higher in those aneurysms that extended into the thoracic aorta, which explained the observed variability in aneurysm shape. Conclusions Our results are the first to describe apparent luminal dilatation, suprarenal branch ruptures and intramural hematoma formation in dissecting abdominal aortic aneurysms in mice. Moreover we validate and demonstrate the vast potential of phase contrast X-Ray tomographic microscopy in cardiovascular small animal applications.
    Cardiovascular Research 12/2014; 105(2). DOI:10.1093/cvr/cvu257 · 5.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Vascular homeostasis is regulated by complex interactions between many vascular cell components, including endothelial cells, vascular smooth muscle cells (VSMCs), adventitial inflammatory cells, and autonomic nervous system. The balance between oxidant and antioxidant systems determines intracellular redox status, and their imbalance can cause oxidative stress. Excessive oxidative stress is one of the important stimuli that induce cellular damage and dysregulation of vascular cell components, leading to vascular diseases through multiple pathways. Cyclophilin A (CyPA) is one of the causative proteins that mediate oxidative stress-induced cardiovascular dysfunction. CyPA was initially discovered as the intracellular receptor of the immunosuppressive drug cyclosporine 30 years ago. However, recent studies have established that CyPA is secreted from vascular cell components, such as endothelial cells and VSMCs. Extracellular CyPA augments the development of cardiovascular diseases. CyPA secretion is regulated by Rho-kinase, which contributes to the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, and heart failure. We recently reported that plasma CyPA levels are significantly higher in patients with coronary artery disease, which is associated with increased numbers of stenotic coronary arteries and the need for coronary intervention in such patients. Furthermore, we showed that the vascular erythropoietin (Epo)/Epo receptor system plays an important role in production of nitric oxide and maintenance of vascular redox state and homeostasis, with a potential mechanistic link to the Rho-kinase-CyPA pathway. In this article, I review the data on the protective role of the vascular Epo/Epo receptor system and discuss the roles of the CyPA/Rho-kinase system in cardiovascular diseases.
    The Tohoku Journal of Experimental Medicine 01/2015; 235(1):1-15. DOI:10.1620/tjem.235.1 · 1.28 Impact Factor