Targeting Macrophage Phenotypes and Metabolism as Novel Therapeutic Approaches in Atherosclerosis and Related Cardiovascular Diseases

Abstract

Purpose of the review: Macrophage accumulation and activation function as hallmarks of atherosclerosis and have complex and intricate dynamics throughout all components and stages of atherosclerotic plaques. In this review, we focus on the regulatory roles and underlying mechanisms of macrophage phenotypes and metabolism in atherosclerosis. We highlight the diverse range of macrophage phenotypes present in atherosclerosis and their potential roles in progression and regression of atherosclerotic plaque. Furthermore, we discuss the challenges and opportunities in developing therapeutic strategies for preventing and treating atherosclerotic cardiovascular disease.

Recent findings: Dysregulation of macrophage polarization between the proinflammatory M1 and anti-inflammatory M2 phenotypealters the immuno-inflammatory response during atherosclerosis progression, leading to plaque initiation, growth, and ultimately rupture. Altered metabolism of macrophage is a key feature for their function and the subsequent progression of atherosclerotic cardiovascular disease. The immunometabolism of macrophage has been implicated to macrophage activation and metabolic rewiring of macrophages within atherosclerotic lesions, thereby shifting altered macrophage immune-effector and tissue-reparative function. Targeting macrophage phenotypes and metabolism are potential therapeutic strategies in the prevention and treatment of atherosclerosis and atherosclerotic cardiovascular diseases. Understanding the precise function and metabolism of specific macrophage subsets and their contributions to the composition and growth of atherosclerotic plaques could reveal novel strategies to delay or halt development of atherosclerotic cardiovascular diseases and their associated pathophysiological consequences. Identifying biological stimuli capable of modulating macrophage phenotypes and metabolism may lead to the development of innovative therapeutic approaches for treating patients with atherosclerosis and coronary artery diseases.

Keywords: Atherosclerosis; Coronary artery diseases; Macrophage; Metabolism; Phenotype.

Fig. 1

Phenotypes and metabolic mechanism of macrophages in the progression of atherosclerotic plaque and related cardiovascular diseases. Macrophages with different functional phenotypes are likely to perform different roles in the development of atherosclerosis. Macrophages in early atherosclerotic lesions are predominantly derived from monocytes recruited from the blood cycle. Monocyte adhesion to endothelial cells and migration into the arterial vessel wall, whereas macrophage proliferation and local inflammation are the primary features. With the progression of atherosclerosis, macrophage engulf lipoprotein-derived cholesterol, leading to foam cell formation, macrophage apoptosis, the plaque lesions towards to a vulnerable type known as unstable atherosclerotic plaques with large necrotic cores and thin fibrous caps. Unstable plaques are prone to rupture, which may cause thrombus formation and arterial occlusion contributing to myocardial infarction and sudden cardiac death

Fig. 2

Schematic representation of macrophage immunometabolism pathways. (A) LPS/IFN-γ induced macrophage. The enhanced glycolysis and pentose phosphate pathway, generating NADPH for reactive oxygen species, nitric oxide and a disturbed TCA cycle. (B) IL-4 induced macrophage. An intact TCA cycle resulting in sustained ATP production via oxidative phosphorylation (OXPHOS). ROS, reactive oxygen species; NO, nitric oxide; OXPHOS: oxidative phosphorylation; PPP: pentose phosphate pathway; IL4, interlukin-4; FAO: fatty acid oxidation; TCA, tricarboxylic acid