The role of inflammation in cardiovascular disease and diabetes (DM) has become increasingly evident. Especially, a combination of risk factors such as hypertension, obesity, DM, smoking, hyperlipidemia, and genetic predisposition create a proinflammatory environment that leads to endothelial (EC) dysfunction. This dysfunction is exacerbated by disturbed blood flow (d-flow) against the EC. In the physiological state, normal EC function is maintained with the release of anti-atherosclerotic signals stimulated by laminar/steady blood flow and high shear stress (s-flow). Our data show that p90RSK activation inhibits Sentrin/SUMO- specific proteases 2 (SENP2) de-SUMOylation activity and increases both p53 and ERK5-SUMOylation, which increases p53 nuclear export and enhances the apoptotic function of p53 and inhibits ERK5-transcriptional activity and its anti-inflammatory responses. The major hypothesis is that p90RSK activation in EC at atheroprone areas inhibits ERK5-dependent transcriptional activity and stimulates p53-SUMOylation thereby promoting EC inflammation and apoptosis, especially in DM. The experimental approach will be to define the mechanisms by which p90RSK regulates ERK5, p53, EC inflammation and apoptosis in Aims 1 and 2.
In Aim 3 we will use mutants and inhibitory fragments generated in aims 1 and 2 in well-defined flow environments to prove that we can mitigate the harmful effects of d-flow by inhibiting p90RSK- and SENP2-mediated inflammation and apoptosis.
In Aim 4 we will use genetic mouse models to evaluate the relative roles of p90RSK and SENP2 activity in atherosclerosis. We anticipate that specific d-flow and DM-dependent p90RSK activation and subsequent ERK5 and p53-SUMOylation make EC atheroprone. The proposed studies should provide significant new information regarding two important questions in d-flow and DM-related EC dysfunction: 1. The role of p90RSK activation on SENP2 de-sumoylation activity and subsequent EC apoptosis and inflammation, and 2. The role of p90RSK-mediated ERK5 phosphorylation on EC inflammation. The concept of p90RSK-SENP2 and p90RSK-ERK5 compartmentalization (nucleus vs cytosol) in atherosclerosis is novel and highlights the importance of post-translational mechanisms in disease pathogenesis. The proteins in these pathways should be attractive drug targets since they have unique features that distinguish them from other MAPK and signal events. We believe that our novel small molecule, specific p90RSK inhibitor, should provide a new therapeutic strategy for reducing atherosclerosis in DM.
The role of inflammation in cardiovascular disease and diabetes has become increasingly evident. At the basic science level understanding the specific signaling events involved in these mechanisms is a key issue that will be addressed here by biochemistry, cell biology, and in vivo transgenic mice. These studies should provide insight into mechanisms by which disturbed flow promotes vascular inflammation and facilitate development of new therapeutic approaches to limit atherosclerosis, especially in DM.
|Abe, Jun-ichi; Berk, Bradford C (2014) Novel mechanisms of endothelial mechanotransduction. Arterioscler Thromb Vasc Biol 34:2378-86|
|Le, Nhat-Tu; Takei, Yuichiro; Izawa-Ishizawa, Yuki et al. (2014) Identification of activators of ERK5 transcriptional activity by high-throughput screening and the role of endothelial ERK5 in vasoprotective effects induced by statins and antimalarial agents. J Immunol 193:3803-15|
|Smolock, Elaine M; Burke, Ryan M; Wang, Chenjing et al. (2014) Intima modifier locus 2 controls endothelial cell activation and vascular permeability. Physiol Genomics 46:624-33|
|Heo, Kyung-Sun; Cushman, Hannah J; Akaike, Masashi et al. (2014) ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis. Circulation 130:180-91|
|Abe, Jun-ichi; Berk, Bradford C (2013) Cezanne paints inflammation by regulating ubiquitination. Circ Res 112:1526-8|
|Heo, Kyung-Sun; Chang, Eugene; Le, Nhat-Tu et al. (2013) De-SUMOylation enzyme of sentrin/SUMO-specific protease 2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis. Circ Res 112:911-23|
|Le, Nhat-Tu; Heo, Kyung-Sun; Takei, Yuichiro et al. (2013) A crucial role for p90RSK-mediated reduction of ERK5 transcriptional activity in endothelial dysfunction and atherosclerosis. Circulation 127:486-99|
|Heo, Kyung-Sun; Chang, Eugene; Takei, Yuichiro et al. (2013) Phosphorylation of protein inhibitor of activated STAT1 (PIAS1) by MAPK-activated protein kinase-2 inhibits endothelial inflammation via increasing both PIAS1 transrepression and SUMO E3 ligase activity. Arterioscler Thromb Vasc Biol 33:321-9|
|Abe, Jun-ichi; Berk, Bradford C (2013) Atheroprone flow activation of the sterol regulatory element binding protein 2 and nod-like receptor protein 3 inflammasome mediates focal atherosclerosis. Circulation 128:579-82|
|Le, Nhat-Tu; Takei, Yuichiro; Shishido, Tetsuro et al. (2012) p90RSK targets the ERK5-CHIP ubiquitin E3 ligase activity in diabetic hearts and promotes cardiac apoptosis and dysfunction. Circ Res 110:536-50|
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