Abstract
BackgroundThe beneficial effects of angiotensin II type 1 receptor blockers (ARBs) on atherosclerosis have been demonstrated in numerous studies. We investigated the effects of fimasartan on reducing neointimal formation and systemic inflammation after carotid artery (CA) injury in Apolipoprotein E knockout (ApoE KO) mice.MethodsApoE KO mice were randomly allocated to Group I (without CA injury), Group II (without CA injury + Fimasartan), Group III (CA injury), and Group IV (CA injury + Fimasartan). Fimasartan was orally administered everyday starting 3 days before iatrogenic left CA injury.ResultsAt 28 days, neointimal hyperplasia and the inflammatory cytokines including TNFα, IL-6, ICAM, and MMP-9 in the peripheral blood were significantly reduced in Groups II and IV compared to Groups I and III, respectively.All fimasartan-administered groups revealed significant increases of CD4+CD25+Foxp3+ regulatory T (Treg) cells with increased plasma levels of IL-10 and TGFβ. In addition, increased CD8+ T cells by fimasartan were correlated with reduced smooth muscle cell (SMC) proliferation in the neointima in Groups II and IV. Furthermore, the populations of Treg and CD8+ T cells in total splenocytes were increased in Groups II and IV compared to Groups I and III, respectively. The enlargement of spleens due to CA injury in the Group III was attenuated by fimasartan, as shown in the Group IV. These data indicate that fimasartan significantly reduced SMC proliferation in neointima and increased Treg cells in ApoE KO CA injury mice.ConclusionsThis study suggests fimasartan could be an efficient strategy for reduction of atherosclerotic progression, with a decrease in immune response and systemic inflammation.
Highlights
Angiotensin II (Ang II) is a pivotal component of the reninangiotensin system (RAS) and is mainly regulated by Ang II type 1 (AT1) receptors
Fimasartan administration suppresses neointimal hyperplasia after carotid artery (CA) injury in KO Apolipoprotein E knockout (ApoE) KO mice Neointimal formation in CA was significantly increased by mechanical injury in the Group III (50.06 ± 7.50%) compared to the Group I (12.31 ± 2.97%)
Fimasartan administration and CA injury had no significant effects on the plasma lipid levels with respect to triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL)/VLDL, and total cholesterol (Additional file 1: Table S1)
Summary
Angiotensin II (Ang II) is a pivotal component of the reninangiotensin system (RAS) and is mainly regulated by Ang II type 1 (AT1) receptors. Activation of AT1 receptors by Ang II regulates blood pressure, but affects blood vessel inflammation and endothelial dysfunction in the progression of hypertension and atherosclerosis (Mehta and Griendling 2007). AT1 receptor blockers (ARBs) have been developed to selectively block AT1 receptors and reported to reduce progression of these diseases (Arishiro et al 2007; Matsumura et al 2011). A recent clinical study revealed that mildto-moderate hypertensive patients who were administered fimasartan showed significant reduction in blood pressure compared to those administered Losartan (Lee et al 2012). The beneficial effects of angiotensin II type 1 receptor blockers (ARBs) on atherosclerosis have been demonstrated in numerous studies. We investigated the effects of fimasartan on reducing neointimal formation and systemic inflammation after carotid artery (CA) injury in Apolipoprotein E knockout (ApoE KO) mice
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