Vascular Calcification in Chronic Renal Failure

Abstract

Accelerated atherosclerotic plaque calcification and extensive medial calcifications are common and highly detrimental complications of chronic kidney disease. Valid murine models have been developed to investigate both pathologically distinguishable complications, which allow for better insight into the cellular mechanisms underlying these vascular pathologies and evaluation of compounds that might prevent or retard the onset or progression of vascular calcification. This review describes various experimental models that have been used for the study of arterial intimal and/or medial calcification and discusses the extent to which this experimental research has contributed to our current understanding of vascular calcification, particularly in the setting of chronic renal failure. (Circ Res. 2011;108:249-264.) Key Words: animal models Ⅲ vascular calcification Ⅲ chronic renal failure C ardiovascular disease is the main cause of morbidity and mortality in patients with chronic kidney disease (CKD), accounting for approximately 50% of all deaths in patients on dialysis and in recipients of renal transplants. 1 A large-scale prospective population-based study showed that renal function was inversely associated with cardiovascular and allcause mortality. 2 Vascular calcification is the major cause of cardiovascular disease in patients with CKD as it contributes to myocardial ischemia, impaired myocardial function, valvular insufficiency, arrhythmias and stroke and is shown to be a strong independent predictor of mortality in the general 3,4 as well as in the dialysis population. [5][6][7] In patients with endstage renal disease, the risk of death increases with the number of vascular sites affected by calcification in the aorta and the carotid and femoral arteries. 5 The high prevalence of vascular calcification is already reported in early stages of CKD 8,9 and in young dialysis patients. 10,11 Atherosclerotic plaque burden in the intimal layer is higher and these lesions are also more heavily calcified in CKD patients compared to the normal population. 12-14 Although intimal calcification is associated with cardiovascular mortality, 6 it remains controversial whether calcification of advanced atherosclerotic lesions stabilizes plaque vulnerability [15][16][17] or rather contributes to rupture of the fibrous cap, 18,19 leading to thrombotic events and myocardial infarction. Interestingly, Ehara et al 20 nicely showed that the pattern of calcification in the intimal plaque is of importance: small, frequent, spotty calcifications are more often found in patients with an acute myocardial infarction or with unstable angina pectoris, whereas the presence of extensive calcifications was highest in those with stable angina pectoris. Recent investigations add new insights to this observation and indicate that, in contrast to spacious calcified areas, sparse microcalcifications produce local stress, 21 activate macrophages to secrete inflammatory mediators 22 and induce apoptosis of vascular smooth muscle cells, 23...

Role of Cellular Cholesterol Metabolism in Vascular Cell Calcification

“…Long considered to be a passive process, there now exists much evidence to suggest that vascular calcification is an active cell-mediated phenomenon that is highly regulated through complex mechanisms under active investigation (4). In vitro and in vivo studies have implicated numerous positive and negative regulatory factors in the pathogenesis of calcification (5)(6)(7)(8).…”

Vascular calcification is coupled with phenotypic conversion of vascular smooth muscle cells through Klf5-mediated transactivation of the Runx2 promoter

“…Within 6 weeks of feeding 0.75% adenine-rich diet, calcification of the tunica media of the aorta was evident with Von Kossa staining. This type of calcification is independent of lipids and seems to be related to the expression of numerous bone-associated proteins [35]. It is generally accepted that dysregulated Ca and P homoeostasis plays a major role in driving VSMC calcification in CRF.…”

Fetuin-A Regulation of Calcified Matrix Metabolism

“…152 Fetuin-A is one of the major systemic inhibitors of pathological mineralization, but it is not the only one. This is vividly illustrated by the history of fetuin-A-deficient mice (Ahsg…”