Atherosclerosis is the primary cause of coronary heart disease (CHD), ischemic stroke, and peripheral arterial disease. Despite effective lipid-lowering therapies and prevention programs, atherosclerosis is still the leading cause of mortality in the United States. Moreover, the prevalence of CHD in developing countries worldwide is rapidly increasing at a rate expected to overtake those of cancer and diabetes. Among prominent risk factors, hardening of arteries resulting from endothelial cell (EC) dysfunction, plays a causative role in promoting atherosclerosis initiation and progression. However, owing to the complexity of the endothelium and scarcity of proper molecular targets, it is widely recognized that hindering dysfunctional endothelium to prevent atheroma progression is a seemingly daunting question. Our long-term goal is to uncover and dissect molecular mechanisms governing endothelial dysfunction, and to aid rapid identification of a new class of potential regulators responsible. To this end, we show that epsins 1 and 2 are upregulated in atheromas in apolipoprotein E-deficient (ApoE-/-) mice fed with western diet (WD). Consequently, EC-specific epsins deficiency results in striking attenuation of atherosclerosis in WD fed ApoE-/- mice. Moreover, we observe that upregulation of epsins associates with downregulation of IP3R1 in both mouse and human atherosclerotic lesions. Interestingly, atherogenic mediators induce epsin binding to IP3R1 and IP3R1 downregulation in endothelial cells. Accordingly, IP3R1 loss augments ER stress, while epsin deficiency prevents IP3R1 loss and therefore attenuates ER stress. Despite these novel observations, whether sufficient IP3R1 is required for keeping ER stress at bay and blocking atheroma progression is unclear. Likewise, whether epsins promote atherosclerosis in part via mediating IP3R1 downregulation is unknown. Given that downregulation of ER stress sensors including XBP-1 correlates with IP3R1 stabilization, the ability of XBP-1 to potentiate ERAD and thereby mediate epsin-dependent IP3R1 degradation is unexplored. In pursuit of answers to these highly significant and original questions, we have formulated the central hypothesis that epsin promotes atherosclerosis by inducing downregulation of IP3R1, exacerbating ER stress, and causing endothelial dysfunction. To test our hypothesis, we propose to use novel atherosclerosis mouse models including inducible EC-specific IP3R1 deficient mice (EC-IP3R1iKO), inducible EC-specific epsin DKO mice (EC-iDKO) on EC- specific IP3R1 heterozygous background (EC-iDKO/EC-IP3R1het), and EC-specific XBP-1 deficient mice (EC- XBP-1KO) on ApoE null background. We are poised to determine the molecular mechanisms underlying epsins mediating IP3R1 degradation in atherosclerosis; and molecular mechanisms by which ER stress sensors potentiate epsin-mediated IP3R1 degradation. If fruitful, our findings will hold a high probability of uncovering a counter-intuitive role for endothelial IP3R1 in atherosclerosis, offering a new class of therapeutic strategies by targeting epsins, and inaugurating a paradigm shift in research to combat atherosclerosis.
Atherosclerosis is the leading cause of heart attack, stroke and even death worldwide; a positive correlation of severity of heart disease with the extend of hardening of arteries, which is caused in part by faulty endothelial cells, building blocks for arteries, accentuates the contribution of defective endothelium in promoting atheroma formation and progression. How to preclude endothelium from damage to stop atherosclerosis is a long- standing but highly medically relevant question. In current application, we will determine how inhibiting epsin function prevents IP3R1 degradation triggered by oxidized lipids, and how blocking pathways facilitating epsin- mediated IP3R1 degradation eases endothelial stress, ultimately, leading to new approaches to treat heart disease. Thus, our work is highly relevant to NHLBI?s mission to reduce the burdens of human heart disease.
| Liu, Limei; Wang, Ying; Wang, Jian et al. (2018) Enhanced hexose-6-phosphate dehydrogenase expression in adipose tissue may contribute to diet-induced visceral adiposity. Int J Obes (Lond) 42:1999-2011 |
| Dong, Jerry; Saunders, Debra; Silasi-Mansat, Robert et al. (2018) Therapeutic efficacy of a synthetic epsin mimetic peptide in glioma tumor model: uncovering multiple mechanisms beyond the VEGF-associated tumor angiogenesis. J Neurooncol 138:17-27 |
| Song, Kai; Fu, Jianxin; Song, Jianhua et al. (2017) Loss of mucin-type O-glycans impairs the integrity of the glomerular filtration barrier in the mouse kidney. J Biol Chem 292:16491-16497 |
