Synergistic protective effects of a statin and an angiotensin receptor blocker for initiation and progression of atherosclerosis

Abstract

Aim 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. Methods 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]. Results 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). Conclusion 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.

The pleiotropic benefits of statins include the ability to reduce CD47 and amplify the effect of pro-efferocytic therapies in atherosclerosis

“…The finding that pro-efferocytic therapies amplify the pleiotropic benefits of statins in mice is therefore interesting, particularly given our translational observation that statin usage is associated with lower vascular CD47 expression in humans. It is also important to note that this observed benefit occurs independent of classical risk factors like hypertension, glucose, and lipid levels, which is consistent with prior reports studying these agents in vascular models 11 , 13 , 33 – 35 . Because pro-phagocytic therapies reduce risk irrespective of traditional risk pathways (which can already be addressed with currently-available medicines), we hypothesize that reactivating intraplaque efferocytosis is an auspicious target for the residual inflammatory risk in atherosclerosis.…”

Angiotensin II, Hypercholesterolemia, and Vascular Smooth Muscle Cells: A Perfect Trio for Vascular Pathology

“…These investigators found that Enalapril up-regulated the expression of the anti-inflammatory transcription factor peroxisome proliferator-activated receptors (PPAR)-gamma, adding mechanistic insight to this study. In one interesting report, a combination strategy was performed in which a statin was administered to hypercholesterolemic rabbits simultaneously with an AT1R blocker [ 62 ]. Plaque burden was inhibited more in the combination group compared with the statin alone group, again pointing to Ang II signaling as a pro-atherogenic event.…”

“…In one randomized clinical trial, elderly human subjects treated with the angiotensin receptor blocker Valsartan demonstrated improved age-related vascular compliance [ 66 ]. In one longitudinal study, carotid artery stiffness was correlated with advancing age [ 62 ], but addition of anti-hypertensive therapy was significantly correlated with improved artery distensibility, linking age, artery stiffness, and hypertension.…”

The Protective Effects of Statins Towards Vessel Wall Injury Caused by a Stent Retrieving Mechanical Thrombectomy Device : A Histological Analysis of the Rabbit Carotid Artery Model

“…Other variables in groups 3 and 4, compared to those in the positive control group, were also substantially reduced, but failed to show statistically significant differences. Since there have been reports that statins exert prohibitory effects on atherosclerotic plaque formation by reducing macrophage content [ 19 , 24 ], the difference in the window period during which the rabbit carotid arteries were harvested between this study (1 week) and previous literature (2 or more weeks) was possibly the reason why our immunohistochemical results failed to show significance.…”