Deletion or Inhibition of NOD1 Favors Plaque Stability and Attenuates Atherothrombosis in Advanced Atherogenesis

Abstract

Atherothrombosis, the main cause of acute coronary syndromes (ACS), is characterized by the rupture of the atherosclerotic plaque followed by the formation of thrombi. Fatal plaque rupture sites show large necrotic cores combined with high levels of inflammation and thin layers of collagen. Plaque necrosis due to the death of macrophages and smooth muscle cells (SMCs) remains critical in the process. To determine the contribution of the innate immunity receptor NOD1 to the stability of atherosclerotic plaque, Apoe−/− and Apoe−/− Nod1−/− atherosclerosis prone mice were placed on a high-fat diet for 16 weeks to assess post-mortem advanced atherosclerosis in the aortic sinus. The proliferation and apoptosis activity were analyzed, as well as the foam cell formation capacity in these lesions and in primary cultures of macrophages and vascular SMCs obtained from both groups of mice. Our results reinforce the preeminent role for NOD1 in human atherosclerosis. Advanced plaque analysis in the Apoe−/− atherosclerosis model suggests that NOD1 deficiency may decrease the risk of atherothrombosis by decreasing leukocyte infiltration and reducing macrophage apoptosis. Furthermore, Nod1−/− SMCs exhibit higher proliferation rates and decreased apoptotic activity, contributing to thicker fibrous caps with reduced content of pro-thrombotic collagen. These findings demonstrate a direct link between NOD1 and plaque vulnerability through effects on both macrophages and SMCs, suggesting promising insights for early detection of biomarkers for treating patients before ACS occurs.

Intermedin1-53 attenuates atherosclerotic plaque vulnerability by inhibiting CHOP-mediated apoptosis and inflammasome in macrophages

“…In late lesions, defective phagocytic clearance of apoptotic macrophages may lead to a proinflammatory response by the inflammasome, accompanied by the generation of the necrotic core 9 – 11 . Increasing evidence suggests that advanced lesion macrophage apoptosis and inflammation is associated with necrotic core expansion and fibrous cap thinning 12 – 14 .…”

High-fat diet activates splenic NOD1 and enhances neutrophil recruitment and neutrophil extracellular traps release in the spleen of ApoE-deficient mice

“…Barcelona, Spain). Double-knockout Apoe −/− Nod1 −/− mice were generated by crossing Apoe −/− mice with Nod1 −/− mice as previously described [ 31 , 32 ]. Only male mice were used for the experiments because these animals are more prone to develop atherogenesis than other genotypes, as previously described [ 32 , 33 ].…”

NOD1-Targeted Immunonutrition Approaches: On the Way from Disease to Health

“…In these circumstances, cells such as macrophages and smooth muscle cells play a critical role since they proliferate, undergo apoptosis, and form foam cells within the plaque. NOD1 is involved in all these processes that contribute to the vulnerability of atheromas [ 58 , 61 ]. Cardiac dysfunction, impaired excitation–contraction coupling, and Ca 2+ handling have also been associated with NOD1 [ 62 ].…”