Chem Immunol. fibrosis and restrictive diastolic filling are commonly described in humans, although mainly after exposures with relatively high doses of radiation [4, 43C46]. The incidence of these alterations after lower dose exposures is not yet known. Data on dose-response relationships of RIHD in animal models are reviewed elsewhere [31, 47]. New technological advances have brought more detailed and minimally invasive methods to study cardiovascular changes in small laboratory animals. Techniques such as high-resolution ultrasound, magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT) are currently in use to assess cardiac structural and functional changes after exposure to radiation in small animals and will undoubtedly contribute to the progress made in the field of experimental RIHD in the coming years. Below we outline the results obtained from pre-clinical studies designed to uncover mechanisms of RIHD. Studies have addressed the roles of endothelial injury, transforming growth factor-beta (TGF-), the renin-angiotensin system (RAS), mast cells, the cardiac sensory nervous system, and endothelin-1 (ET-1) in experimental RIHD. POTENTIAL MECHANISMS OF RIHD: REVIEW OF PRE-CLINICAL STUDIES Endothelial Injury Endothelial dysfunction has been shown to play an important role in the pathogenesis of normal tissue radiation injury, as reviewed elsewhere [48, 49]. Endothelial dysfunction is associated with a loss of thromboresistance and increased expression of chemokines and adhesion molecules and may lead to a pro-fibrotic and pro-inflammatory environment, all likely contributors to manifestations of radiation injury. Several studies suggest that endothelial dysfunction is occurring in RIHD, as experimental RIHD is associated with Givinostat histopathological signs of microvascular injury and reduced myocardial capillary density , focal loss of endothelial alkaline phosphatase [27, 51], and increased expression and deposition of von Willebrand factor . A recent study suggests that altered lipid profiles or other circulating factors may affect radiation-induced changes in the myocardial microvasculature . Hence, although not yet tested in experimental models, pharmacological modifiers of endothelial function, such as statins and certain beta-blockers that are of benefit in many cardiovascular disease states may potentially reduce manifestations of RIHD. TRANSFORMING GROWTH FACTOR-BETA TGF- is a pluripotent growth factor that controls PPP3CA many functions including cell proliferation and differentiation in many cell types. TGF- plays an important role in cardiac hypertrophy and fibrosis [54, 55] and is considered a central growth player in radiation-induced normal tissue fibrosis [56C58] and radiation-induced vascular injury [59, 60]. Previous studies showed upregulation of TGF-, both at the mRNA and the protein level, after local heart irradiation in the rat [61C63]. A TGF-Cinducing compound was used to investigate the role of TGF- in RIHD in the rat. Radiation induced a significant increase in collagen deposition, which was more severe after TGF- induction (unpublished data). To further analyze the role of TGF- in RIHD, studies involving TGF- signaling inhibition are being undertaken. THE RENIN-ANGIOTENSIN SYSTEM The RAS is a major regulatory system of cardiovascular and renal functions, regulating blood volume and Givinostat vascular resistance. In addition to the first discovered circulatory RAS, recent evidence has shown that local tissue RAS plays a significant role in tissue homeostasis and the response to injury . Angiotensin II (Ang II) is a small peptide formed in the RAS after the initial conversion of angiotensinogen to angiotensin I (Ang I) by the enzyme renin. The role of Ang II in cardiac pathophysiology is well known, having been the subject of numerous reviews [65C67]. Ang II can be generated from Ang I by several proteases, of which angiotensin converting Givinostat enzyme (ACE) and mast cell chymase are the main converters . Mast cell chymase seems of particular importance in the local extravascular generation of Ang II . Interestingly, the local cardiac RAS interacts with many other systems in the heart, including the cardiac nervous systems and the endothelin system, and locally generated Ang II appears to contribute to cardiac hypertrophy and fibrosis [70, 71]. The role of RAS in radiation injury in organs other than the heart has been studied extensively and reviewed elsewhere [72, 73]. ACE inhibitors and antagonists of angiotensin type 1 receptors reduce experimental radiation injury in organs such as kidney, lung and brain [74C76]. Studies.