Necrotic core formation in advanced atherosclerotic lesion, which is a collection of dead and necrotic macrophages surrounded by inflammatory cells, contributes to inflammation, plaque disruption, and thrombosis and leads to vulnerable plaque formation. Especially, defective phagocytic clearance (efferocytosis) of dying cells is critically linked to progression of advanced atherosclerotic lesions. Efferocytosis can involve many molecules including find me and eat me signaling molecules and bridging molecules including opsonins, but its comprehesive regulatory mechanism in advanced lesion of atherosclerosis remains unclear. Our data show that addition of apoptotic cells (ACs) activates ERK5 kinase in macrophages and accelerates efferocytosis via secretion of opsonins, whereas these responses are inhibited in macrophages from ERK5 knock-out (ERK5- MKO) mice. Indeed, ERK5-MKO mice showed increased necrotic core and atherosclerosis formation. Since macrophage angiotensin II type 1 receptor (AT1) was involved in efferocytosis, the major hypothesis is that macrophage ERK5 kinase activation by ACs is a key event in efferocytosis in the advanced lesion of atheroslcerosis and p90RSK activation under angiotensin II inhibits efferocytosis by inhibiting ERK5 transcriptional activity. We will experimentally determine the mechanisms by which macrophage ERK5 regulates efferocytosis as a sensor of ACs in Aim 1 and Aim2.
In Aim 3, we will use genetic mouse models to determine the role of macrophage ERK in necrotic core formation in atherosclerotic lesions.
In Aim 4, we will investigate the possible role of macrophage p90RSK in regulating ERK5 activity in efferocytosis and atherosclerosis formation. The significance of our study is in providing a mechanistic understanding of the clinically well-described cardiac risk of acute atherothrombotic vascular disease in advanced atherosclerotic lesions. Understanding the role and molecular mechanisms of ERK5-mediated efferocytosis as well as inhibition of necrotic core and atherosclerosis formation should provide insights into the cause of acute atherothrombotic vascular diseases in advanced lesion and possibly reveal a novel therapeutic targets.
The key role of efferocytosis in atherosclerosis and the stability of vulnerable plaques have become increasingly evident. We anticipate that specific macrophage ERK5 downregulation and subsequent reduced expression of ERK5 targeted molecules including efferocytosis-related genes make macrophages atheroprone and form a vulnerable plaque accumulating apoptotic debris and necrotic core. Mechanistically, we have found that p90RSK regulates the ERK5 effects on the efferocytosis process as a negative regulator. Therefore, the activation of ERK5 and inhibition of p90RSK activity could emerge as novel therapeutic targets to tackle the highly relevant problem of managing vulnerable plaques from rupture.
| Le, Nhat-Tu; Abe, Jun-Ichi (2018) MicroRNA 199a and the eNOS (Endothelial NO Synthase)/NO Pathway. Arterioscler Thromb Vasc Biol 38:2278-2280 |
| Ko, Kyung Ae; Wang, Yin; Kotla, Sivareddy et al. (2018) Developing a Reliable Mouse Model for Cancer Therapy-Induced Cardiovascular Toxicity in Cancer Patients and Survivors. Front Cardiovasc Med 5:26 |
| Venkatesulu, Bhanu Prasad; Mahadevan, Lakshmi Shree; Aliru, Maureen L et al. (2018) Radiation-Induced Endothelial Vascular Injury: A Review of Possible Mechanisms. JACC Basic Transl Sci 3:563-572 |
| Ko, Kyung Ae; Fujiwara, Keigi; Krishnan, Sunil et al. (2017) En Face Preparation of Mouse Blood Vessels. J Vis Exp : |
| Le, Nhat-Tu; Sandhu, Uday G; Quintana-Quezada, Raymundo A et al. (2017) Flow signaling and atherosclerosis. Cell Mol Life Sci 74:1835-1858 |
| Abe, Jun-Ichi; Sandhu, Uday G; Hoang, Nguyet Minh et al. (2017) Coordination of Cellular Localization-Dependent Effects of Sumoylation in Regulating Cardiovascular and Neurological Diseases. Adv Exp Med Biol 963:337-358 |
| Le, Nhat-Tu; Martin, James F; Fujiwara, Keigi et al. (2017) Sub-cellular localization specific SUMOylation in the heart. Biochim Biophys Acta Mol Basis Dis 1863:2041-2055 |
| Mao, Yun; Luo, Wei; Zhang, Lin et al. (2017) STING-IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity. Arterioscler Thromb Vasc Biol 37:920-929 |
| Chang, Eugene; Abe, Jun-Ichi (2016) Kinase-SUMO networks in diabetes-mediated cardiovascular disease. Metabolism 65:623-33 |
| Abe, Jun-Ichi; Martin, James F; Yeh, Edward T H (2016) The Future of Onco-Cardiology: We Are Not Just ""Side Effect Hunters"". Circ Res 119:896-9 |
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