Telmisartan Exerts Antiatherosclerotic Effects by Activating Peroxisome Proliferator-Activated Receptor-γ in Macrophages

Abstract

Objective-Telmisartan, an angiotensin type I receptor blocker (ARB), protects against the progression of atherosclerosis.Here, we investigated the molecular basis of the antiatherosclerotic effects of telmisartan in macrophages and apolipoprotein E-deficient mice. Methods and Results-In macrophages, telmisartan increased peroxisome proliferator-activated receptor-␥ (PPAR␥) activity and PPAR ligand-binding activity. In contrast, 3 other ARBs, losartan, valsartan, and olmesartan, did not affect PPAR␥ activity. Interestingly, high doses of telmisartan activated PPAR␣ in macrophages. Telmisartan induced the mRNA expression of CD36 and ATP-binding cassette transporters A1 and G1 (ABCA1/G1), and these effects were abrogated by PPAR␥ small interfering RNA. Telmisartan, but not other ARBs, inhibited lipopolysaccharide-induced mRNA expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-␣, and these effects were abrogated by PPAR␥ small interfering RNA. Moreover, telmisartan suppressed oxidized low-density lipoproteininduced macrophage proliferation through PPAR␥ activation. In apolipoprotein E Ϫ/Ϫ mice, telmisartan increased the mRNA expression of ABCA1 and ABCG1, decreased atherosclerotic lesion size, decreased the number of proliferative macrophages in the lesion, and suppressed MCP-1 and tumor necrosis factor-␣ mRNA expression in the aorta. Conclusion-Telmisartan

High-Dose Treatment With Telmisartan Induces Monocytic Peroxisome Proliferator-Activated Receptor-γ Target Genes in Patients With the Metabolic Syndrome

“…EXP-3179, the PPAR␥-activating metabolite of losartan, was shown to reach adequate plasma concentrations to induce PPAR␥ target genes in monocytes from patients chronically treated with 100 mg/d of losartan. 23 Furthermore, Matsumura et al 24 showed recently that telmisartan activates PPAR␥ in macrophages exerting antiatherosclerotic actions. The present study investigated PPAR␥ activation in blood monocytes.…”

“…24,34 Thus, induction of CD36 by high-dose telmisartan associated with higher LDL cholesterol levels may be counteracted by a parallel regulation of cholesterol efflux from lesional macrophages resulting in the observed antiatherosclerotic actions of this drug. 24 Furthermore, the results regarding LDL cholesterol levels are somewhat surprising, because previous studies have shown that ARBs either have no effect or decrease LDL cholesterol. 15,28,[35][36][37][38] In fact, all of the studies using telmisartan did show a positive effect.…”

Lactobacillus acidophilus ATCC 4356 Prevents Atherosclerosis via Inhibition of Intestinal Cholesterol Absorption in Apolipoprotein E-Knockout Mice

“…After 16 weeks of treatment, the mice were sacrificed, and atherosclerotic lesions of the aortic sinus were prepared for immunohistochemistry as described below. The whole aorta or 6-m-thick frozen sections of the aortic sinus were obtained from ApoE Ϫ/Ϫ mice and were stained with Oil Red O, as previously described (18). The lesion size was measured on digital microphotographs of the aortic sinus by measuring the stained surface area using ImageJ software (NIH, Bethesda, MD).…”

Agoniści receptorów aktywowanych proliferatorami eroksysomów w farmakoterapii. Obecne znaczenie i perspektywy zastosowania

“…Telmisartan -antagonista receptorów AT1 dla angiotensyny II -jest rów-nież częściowym agonistą PPAR-γ monocytów, a pobudzenie tego receptora powoduje zahamowanie ekspresji genu kodującego główne białko chemoatraktantowe (chemotaktyczne) monocytów [53]. Ponadto, w badaniach eksperymentalnych telmisartan poprzez wpływ na PPAR-γ zmniejszał włóknienie i przebudowę struktury tkankowej wątroby wskutek zahamowania hepatocytarnego czynnika wzrostowego [54].…”

“…Ponadto, w badaniach eksperymentalnych telmisartan poprzez wpływ na PPAR-γ zmniejszał włóknienie i przebudowę struktury tkankowej wątroby wskutek zahamowania hepatocytarnego czynnika wzrostowego [54]. Ujawnione dodatkowe właściwości telmisartanu pozwalają zatem na przypisanie temu związkowi również działania przeciwmiażdżycowego i stabilizującego blaszkę miażdżycową wskutek zmniejszania naciekania komórkowego zmiany miażdżycowej [53,54] i umożliwiają dalsze prowadzenie badań nad potencjalnym zastosowaniem telmisartanu w leczeniu zwłóknienia wątroby [55,56].…”