Mechanisms and Therapeutic Options for Atherosclerosis

Cardiovascular disease is dramatically increased across the entire spectrum of patients with chronic kidney disease. Angiotensin II has a role in renal damage-induced acceleration of atherosclerosis with hypertension in apolipoprotein E deficient (apoe-/-) mice. Losartan, an AII receptor antagonist (ARB), reduces uninephrectomy (UNx)-induced acceleration of atherosclerosis in apoe-/- mice. Losartan also modurates macrophage chemotaxis, cholesterol efflux and inflammation in vitro. We examined if peroxisome proliferator activated receptor γ (PPAR γ) agonist benefits UNx-induced acceleration of atherosclerosis and the possibility of a synergistic interaction with ARB. UNx mice were treated with pioglitazone (a PPAR γ agonist), losartan (an ARB), or both. UNx significantly increased atherosclerosis in proximal aorta which was lessened by pioglitazon and losartan, but especially by the combination which was significantly less than pioglitazone or losartan alone. Assessment of the plaque lesions revealed significantly less necrotic plaque area in the lesion with pioglitazon and losartan treatment. Notably, the macrophage area of combination treatment with pioglitazon and losartan had lesser number of pro-inflammatory M1 phenotype and greater number of alternatively anti-inflammatory M2 phenotype. Those results suggest that ARB especially together with PPAR γ agonist modurates macrophage functions in renal-injury-induced acceleration of atherosclerotic lesion. Therapeutic interventions for hypertension should be considered to modulate progressive atherosclerosis, especially macrophage function