Date Published: May 3, 2019
Publisher: Public Library of Science
Author(s): Seul-Gee Lee, Seung-Jun Lee, Nguyen Viet Phuong Thuy, Jung-Sun Kim, Jung-Jae Lee, Oh-Hyun Lee, Choong-Ki Kim, Jaewon Oh, Seil Park, Ok-Hee Lee, Se Hoon Kim, Sungha Park, Sang-Hak Lee, Sung-Jin Hong, Chul-Min Ahn, Byeong-Keuk Kim, Young-Guk Ko, Donghoon Choi, Myeong-Ki Hong, Yangsoo Jang, Michael Bader.
Although the atheroprotective effects of statins and angiotensin II receptor blockers (ARBs) are well-established, little is known about their additive effects, especially during the early period of atherosclerosis. The aim of this study was to investigate whether combination of a statin and an ARB exerts synergistic anti-atherosclerotic effects, and to elucidate the mechanisms of combined effects.
Atherosclerotic plaques were developed in arteries of 23 rabbits using a high-cholesterol diet (HCD) and intra-arterial balloon inflation. Rabbits received one of five different treatment strategies for 4 weeks: positive control [n = 5, HCD]; negative control [n = 3, regular chow diet]; statin [n = 5, HCD and rosuvastatin 10 mg]; ARB [n = 5, HCD and olmesartan 20 mg]; and combination [n = 5, HCD and statin+ARB].
Histological analysis demonstrated that development of atherosclerotic plaques was inhibited more in combination group than in statin group (P = 0.001). Although macrophage infiltration identified by RAM11 staining was not significantly different between combination and individual treatment groups (31.76±4.84% [combination] vs. 38.11±6.53% [statin; P = 0.35] or 35.14±2.87% [ARB; P = 0.62]), the relative proportion of pro-inflammatory M1-macrophages was significantly lower in combination group than in ARB group (3.20±0.47% vs. 5.20±0.78%, P = 0.02). Furthermore, M2-macrophage polarization was higher in combination group than in statin group (17.70±3.04% vs. 7.86±0.68%, P = 0.001).
Combination treatment with a statin and an ARB produced synergistic protective effects for atherosclerosis initiation and progression, which may be attributed to modulation of macrophage characteristics in the early period of atherosclerosis.
Cardiovascular diseases (CVDs) are the leading cause of death worldwide . They are primarily caused by atherosclerosis, a composite of complex inflammatory and immunologic responses resulting in atheromatous plaques within the lining of arteries [2–4]. Following lipid accumulation, robust inflammatory responses occur within the intima, producing endothelial injury and dysfunction . During these inflammatory processes, subsets of monocytes play substantial roles in the progression of atherosclerosis and evolve into various phenotypes of macrophages, promoting or inhibiting plaque development . Macrophages involved in the progression of atherosclerosis have different effects on atherosclerosis, according to their polarity. While pro-inflammatory macrophages (M1-type) are usually enriched in progressing plaques, M2-macrophages, which promote tissue repair, are more enriched in regressing plaques [6,7].
This study demonstrated that the combination of a statin and an ARB synergistically exerts early anti-atherosclerotic effects, compared to administration of each drug separately. Further, regulation of macrophage polarization appears to play an important mechanistic role in these synergistic effects (Fig 7).