Despite great strides in understanding the atherogenesis process, the mechanisms are not entirely known. In addition to diet, smoke, genetic predisposition, and hypertension, hyperhomocysteinemia (HHcy), an accumulation of the noncoding sulfur-containing amino acid homocysteine (Hcy), is a significant contributor to atherogenesis. Although exercise decreases HHcy and increases longevity, the complete mechanism is unclear. In light of recent evidence, in this review we focus on the effects of HHcy on macrophage function, differentiation, and polarization. Though there is need for further evidence, it is most likely that HHcy-mediated alterations in macrophage function are important contributors to atherogenesis, and HHcy-countering strategies, such as nutrition and exercise, should be included in the combinatorial regimens for effective prevention and regression of atherosclerotic plaques. Therefore, we also included a discussion on the effects of exercise on the HHcy-mediated atherogenic process.

Oxidized phospholipids (OxPL) are abundant in atherosclerotic plaques. They are also bound to circulating plasminogen after myocardial infarction (MI), and their binding to plasminogen may accentuate fibrinolysis. We sought to assess whether circulating levels of plasminogen and OxPL bound to plasminogen (OxPL-PLG) increase following acute MI and whether this increase differs between atherothrombotic (Type 1) and non-atherothrombotic (Type 2) MI. We measured circulating levels of plasminogen and OxPL-PLG at 0, 6, 24, 48 h, and >3 months (stable state) following acute MI and following an angiogram for stable coronary artery disease (CAD). Forty-nine subjects met the criteria for acute MI, of whom 34 had clearly defined atherothrombotic (n = 22) or non-atherothrombotic (n = 12) MI; 15 patients met the criteria for stable CAD. Mean baseline levels of plasminogen and OxPL-PLG were lower in the acute MI group than in the stable CAD group (9.75 vs 20.2, p < 0.0001 for plasminogen and 165.5 vs 275.1, p = 0.0002 for OxPL-PLG) and did not change over time or between time points, including the 3-month follow-up. Mean baseline levels of plasminogen and OxPL-PLG were also lower in atherothrombotic (Type 1) than in non-atherothrombotic (Type 2) MI subjects (8.65 vs 12.1, p < 0.03 for plasminogen and 164.5 vs 245.7, p = 0.02 for OxPL-PLG), and this relationship did not change over time or between time points. Plasminogen and OxPL-PLG were lower in patients presenting with an acute MI than in those with stable CAD and also in those with atherothrombotic MI (Type 1) vs. those with non-atherothrombotic MI (Type 2). These findings persisted at a median follow-up of 3 months post-MI. The association of plasminogen and OxPL-PLG with acute MI, particularly atherothrombotic MI (Type 1), could reflect a reduced fibrinolytic capacity, associated with an increased risk of atherothrombotic events differentiating stable CAD from unstable CAD and atherothrombotic MI (Type 1) from non-atherothrombotic MI (Type 2). Additional study with a larger sample size is warranted.

Although atherosclerotic plaque rupture is the leading cause of myocardial infarction, the mechanisms are unclear. Macrophages burdened with oxidized LDL (oxLDL) become foam cells: hallmarks of plaque progression and instability. One of the main macrophage-specific receptors for oxLDL is CD68. Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated lactonase capable of retarding/inhibiting LDL oxidation. Elevated levels of homocysteine (Hcy), an amino acid homologue and independent cardiovascular risk factor, is metabolized by Pon1. Given the literature connections of oxLDL, Pon1, Hcy, and macrophages to atherosclerosis, we hypothesized that Pon1 is produced by murine macrophages and its expression is increased by Hcy via CD68. Murine J774a.1 macrophages were treated with LDL, oxLDL, Hcy, or oxLDL+Hcy. Also, separate treatment groups included macrophages that had CD68 silenced by CD68 siRNA transfection. Cell lysates were analyzed for CD68 and Pon1 expression via Western blotting. Pon1 is present in macrophages. Hcy along with oxLDL significantly increases Pon1 (51%, 1.51 vs 0.97) expression compared to controls than oxLDL alone. Pon1 expression is significantly decreased (33%, 0.67 vs 1) with silencing of CD68. Pon1 expression is significantly decreased more with oxLDL (82% 0.17 vs 1) in presence of CD68 silencing but is significantly increased with oxLDL+Hcy (24% 1.24 vs 1). CD68 expression tends to increase more with oxLDL+Hcy than oxLDL alone when compared to control and the tendency follows with silencing of CD68. Our results conclude that Hcy increases macrophage-derived Pon1 expression independent of CD68.