Macrophages in Cardiovascular Diseases

Although the mortality rate from cardiovascular disease (CVD) has declined over the last 50 years, CVD is the leading cause of mortality and morbidity worldwide, especially in the elderly. CVD includes atherosclerosis, ischemic heart disease, cerebrovascular disease, hemorrhagic stroke, hypertensive heart disease, cardiomyopathy, myocarditis, atrial fibrillation, aortic aneurysm, peripheral vascular disease, and endocarditis. Risk factors of cardiovascular disorders are associated with changes in inflammatory response or hematopoiesis. Macrophage-induced inflammation is involved in nearly all CVDs, including atherosclerosis (AS), pulmonary arterial hypertension (PAH), stroke, and cardiac diseases.

Macrophages and CVDs

Macrophages are innate immune cells that reside and accumulate in healthy and damaged hearts, and those cells play a pivotal role during both myocardial tissue damage and repair. Macrophage accumulation is not only a characteristic of PAH but also a key component of pulmonary artery remodeling associated with PAH. During myocardial infarction (MI), AS and stroke, monocytes are supplied by medullary and extramedullary hematopoiesis in bone marrow and spleen. Monocytes infiltrate diseased tissues, differentiate into macrophages and proliferate locally. Angiogenesis and healing of the infarcted heart after damage are promoted by cardiac macrophages derived from the early embryonic cells. Arterial macrophages in AS persist. In AS, macrophage uptake of oxidized lipoprotein exceeds the formation of cholesterol, leading to the accumulation of cholesterol esters, eventual development of foam cells, and plaque development, leading to stroke finally. Perivascular macrophages may play a role in hypertension, specifically the neurological symptoms and cognitive impairment associated with chronic hypertension.

Fig.1 Macrophages in cardiovascular disease. (Honold, 2018)

The Phenotypes of Macrophage in CVDs

Macrophages are composed of two main phenotypes: M1 and M2 macrophage. In AS, M1 macrophages are correlated to plaque vulnerability. Generally, M2 macrophages can activate vascular remodeling and M1 macrophages increase perivascular inflammation, vascular permeability, and fibrosis. Therefore, the presence of M2 macrophages is associated with the progression of PAH and the proliferation of pulmonary artery smooth muscle cells. M1-polarized macrophages are typically found during the early stage of myocardial infarction (MI) leading to acute pro-inflammatory and immune polarization reactions. M1 macrophages can aggravate insult after MI and increase the occurrence of ventricular tachycardia which contributes to ventricular arrhythmias. While M2-polarized macrophages are present during the terminal stages of MI to increase myocardial tissue repair. M2 macrophages with anti-inflammatory and antifibrosis effects reduce rapid morbidity from ventricular tachycardia after MI.

Fig.2 Potential mechanism underlying the regulation of macrophages in cardiovascular disease. (Wei, 2020)

Strategies of Targeting Macrophages in CVD

For each class of CVD, there are some common drugs and targeting strategies used to potentiate therapeutic effects.

• Depletion or inactivation of macrophages is a potential route to reduce inflammation and delay the progression of CVD. Some reports demonstrated that the delivery of clodronate by liposomes eliminated macrophages. Blockage of macrophage-derived cytokines is another potential approach to remove CD68+ macrophages and retard PAH development.
• Reprogramming of macrophages toward M2 phenotypes is one potential strategy to treat AS and cardiac diseases such as myocarditis. While inhibition of macrophages by reduced expression of interleukin 21 (IL-21) can ameliorate PAH.
• Reducing the blood-derived monocyte recruitment and infiltration is beneficial to limit inflammation or atherosclerotic plaque progression after PAH, AS, MI and myocardial fibrosis (MF). Targeted delivery of anti-oxidative agents to macrophages to inhibit the secretion of pro-inflammatory factors, such as reactive oxygen species (ROS), tumor necrosis factor (TNFα), IL-1β, and monocyte chemoattractant protein-1 (MCP-1), is a well-demonstrated strategy to induce regression of AS.

More Details

• Macrophages in Atherosclerosis (AS)
• Macrophages in Pulmonary arterial Hypertension (PAH)
• Macrophages in Cardiac Diseases

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References

1. Honold, L.; Nahrendorf, M. Resident and monocyte-derived macrophages in cardiovascular disease. Circulation Research. 2018, 122(1):113-127.
2. Wei, H.; et al. Drug delivery to macrophages: A review of targeting drugs and drug carriers to macrophages for inflammatory diseases. Advanced Drug Delivery Reviews. 2020, 165-166:15-40.