Effects of Losartan and Simvastatin on Monocyte-Derived Microparticles in Hypertensive Patients With and Without Type 2 Diabetes Mellitus

Abstract

Monocyte-derived microparticles play an important role in the pathogenesis of diabetic vasculopathy, and angiotensin II receptor blocker and statin have been shown to have a beneficial effect on the angiopathies of hypertension and hyperglycemia in patients with type 2 diabetes mellitus. However, the interaction between angiotensin II receptor blocker and statin, and monocyte-derived microparticles in atherosclerosis is poorly understood. The effects of losartan and simvastatin on circulating concentrations of monocyte-derived microparticles, chemokines, and soluble adhesion markers were studied in hypertensive patients with or without type 2 diabetes mellitus. Monocyte-derived microparticles were measured by flow cytometry, and levels of serum chemokines (MCP-1 and RANTES) and soluble adhesion markers (sP-selectin and sVCAM-1) were measured by enzyme-linked immunosorbent assay. Losartan decreased both the systolic and diastolic blood pressure in hypertensive patients with and without type 2 diabetes mellitus. The concentrations of monocyte-derived microparticles, chemokines, and soluble adhesion molecules were higher in hypertensive patients who also had type 2 diabetes mellitus vs. those who did not. The administration of angiotensin II receptor blocker decreased the circulating concentration of all these markers. In addition, all markers were decreased by combination therapy, and monocyte-derived microparticles were decreased more with combination therapy with losartan and simvastatin than monotherapy with losartan. The administration of angiotensin II receptor blocker inhibited monocyte-derived microparticle generation and suggests that angiotensin II is intimately related to vascular changes that occur in type 2 diabetes mellitus. Combination therapy with a statin and angiotensin II receptor blocker might be valuable as anti-atherosclerotic therapy in patients with type 2 diabetes mellitus and nephropathy.

Microvesicles and diabetic complications — novel mediators, potential biomarkers and therapeutic targets

“…[124] . A few studies have indicated that the levels of monocyte-derived MVs [14,55] , endothelial-derived MVs [74] , and platelet-derived MVs [70,125,126] are increased in patients with diabetic nephropathy. The increase in monocyte-derived MVs is most significant in patients with diabetic nephropathy among the T2DM patients with diabetic microangiopathy, ie, nephropathy, retinopathy, or neuropathy [14] .…”

“…The increase in monocyte-derived MVs is most significant in patients with diabetic nephropathy among the T2DM patients with diabetic microangiopathy, ie, nephropathy, retinopathy, or neuropathy [14] . Elevated levels of endothelial-derived MVs and monocytederived MVs may serve as biomarkers for nephropathy progression in T2DM [14,55,74] . A recent study showed that MVassociated dipeptidyl peptidase-IV (DPP-IV) is the major form of DPP-IV in urine, which is secreted from tubular epithelial cells and is related to early tubular impairment [127] .…”

“…The circulating platelet-derived MVs [70,125,126] , monocyte-derived MVs [14,55] , endothelial-derived MVs [74] , and MVs derived from renal mesangial cells [82] may act as mediators and influence endothelial function by simulating the release of cytokines and the expression of various adhesion molecules by endothelial cells, inducing the morphological changes that lead to angiogenesis induction in microvascular endothelial cells.…”

“…An experiment showed that sarpogrelate improves ROS/NO imbalance and suppresses platelet aggregation in glomeruli, which may be associated with reduced circulating platelet-derived MVs [125] . Administration of angiotensin II receptor blockers can decrease circulating monocyte-derived MVs, chemokines (monocyte chemoattractant protein 1 and RANTES), and soluble adhesion markers (soluble P-selectin and sVCAM-1) [55] . The ability of angiotensin II receptor blockers to inhibit monocyte-derived MV generation might be an additional protective mechanism beyond the blood pressure-lowering effects in T2DM.…”

“…Procoagulant platelet-derived MVs [47,48] , monocytederived MVs [14] , and endothelial-derived MVs [49] are significantly increased in patients with diabetes, even in wellcontrolled DM without complications [50] and newly diagnosed T2DM [51] . In addition, patients with diabetes accompanied by hyperten sion [15,16,32,[52][53][54][55][56][57] , hyperlipidemia [58][59][60] , stable coronary disease [61] , angina with [62] or without [17] symptomatic episodes, myocardial infarction [49,63] , diabetic retinopathy, and nephropathy [33,64] have significantly increased levels of procoagulant MVs compared with those without diabetic complications. Therefore, elevated levels of MVs may be associated with the increased risk of thrombo-embolic diabetic complications.…”