Secreted Protein Acidic and Rich in Cysteine (SPARC) Induced by the Renin–Angiotensin System Causes Endothelial Inflammation in the Early Stages of Hypertensive Vascular Injury

Secreted protein acidic rich in cysteine (SPARC), one of the extracellular matrix proteins, is highly induced during inflammation. We investigated the pathophysiological regulation and role of SPARC in vascular inflammation in a rat model of hypertension created using deoxycorticosterone acetate (DOCA, 40 mg/kg/week, s.c.) and salt (1% in drinking water). DOCA-salt administration time-dependently increased systolic blood pressure during the 3-week treatment period, blunted endothelium-dependent vasodilation, and increased monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression in the aorta. SPARC expression transiently increased until week 2 in the DOCA-salt rat aorta. Interestingly, aortic SPARC levels correlated with blood pressure and the levels of MCP-1 and LOX-1 during 0-2 weeks. The AT₁ receptor blocker, losartan, suppressed the overexpression of SPARC, and in vitro treatment with angiotensin II enhanced the production of SPARC in rat aortic endothelial cells. Exposure to recombinant SPARC protein induced overexpression of MCP-1 and LOX-1 mRNA in endothelial cells. Bioactive forms of a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1), excessive activation of which contributes to pathological states and overexpression of which is reported to be induced by SPARC, were increased in the DOCA-salt rat aorta. These results suggest that SPARC is induced by the vascular renin-angiotensin system and causes inflammation in the early stages of hypertensive vascular injury, and that activation of ADAMTS1 might be related to the proinflammatory effects of SPARC.