Mechanisms of Aortic and Cardiac Dysfunction in Uremic Mice With Aortic Calcification

Abstract

Background-Chronic renal failure (CRF) is associated with cardiac dysfunction and increased aortic stiffness. The mechanisms involved are not clearly understood. We examined changes over time in cardiac and aortic function in a murine CRF model. Methods and Results-Eight-week-old mice were randomly assigned to 1 of 4 groups: wild-type non-CRF, wild-type CRF, apolipoprotein E knockout non-CRF, and apolipoprotein E knockout CRF. Echocardiography was performed and blood samples were taken at baseline and after 6 and 10 weeks of CRF. Vascular reactivity and adhesion molecule expression were studied after 6 and 10 weeks of CRF. Left ventricular hypertrophy, altered left ventricular relaxation, and increased aortic stiffness were observed after 6 weeks of CRF and persisted after 10 weeks. The 4 groups of mice did not significantly differ in terms of arterial blood pressure and aortic structure. The degree of vascular calcification and serum total cholesterol concentration were higher in the CRF groups than in the non-CRF groups. These changes, however, could not explain the cardiac and vascular differences seen in the 2 CRF groups. In contrast, alterations in vascular reactivity, the upregulation of adhesion molecule expression, and CRF status were significantly associated with these changes. Conclusions-In a mouse model of CRF, left ventricular hypertrophy, cardiac diastolic dysfunction, and increased aortic stiffness were not related to structural changes in the aorta (including aortic calcification) or high serum cholesterol levels. However, cardiac and aortic abnormalities were associated with the extent of subendothelial dysfunction and the severity of CRF.

Chronic renal failure alters endothelial function in cerebral circulation in mice

“…We hypothesized that endothelium-dependent relaxation would be impaired in cerebral arterioles, as previously observed in the aorta (24).…”

“…The rationale for using female mice and two different strains is based on the observation that male and female WT mice do not develop calcification during CRF. In contrast, ApoE Ϫ/Ϫ mice develop arterial calcification during CRF (24), but the process is much slower in males than in females. Since vascular calcification may affect vascular structure and function, we wondered whether this would be true for the cerebral circulation.…”

“…In view of our observation that endothelial dysfunction in the aorta results in an increase in aortic rigidity, we hypothesized that endothelial dysfunction would be accompanied by alterations in the structure and distensibility of cerebral arterioles (24).…”

A Murine Model of Phosphate Nephropathy

“…The positive phosphate balance seems to cause an accelerated progression of vascular calcification. [5][6][7][8] An acute phosphate load that overwhelms renal capacity for excretion can be derived from endogenous and exogenous sources. Large amounts of endogenous phosphates are released from intracellular stores in tumor lysis syndrome, rhabdomyolysis, and lactic acidosis.…”

Short-term hyperglycaemia causes non-reversible changes in arterial gene expression in a fully ‘switchable’ in vivo mouse model of diabetes

“…We found that 769 genes were differentially expressed by the peak of hyperglycaemia, including a very important group implicated in arterial calcification and premature atherosclerosis [34][35][36][37]. Other genes included those involved in cell cycle, cell adhesion, antioxidant processes, inflammation and angiogenesis, and those encoding molecules involved in endothelial and smooth muscle cell function.…”