Pim1 kinase coordinates PPAR gamma pathway and mitochondrial function to mediate pro-atherogenic responses in macrophages

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Atherosclerosis (AS) remains the leading cause of death world-wide and it is often associated with dyslipidemia, oxidative stress and mitochondrial dysfunction. Macrophage is a type of innate immune cell that plays a critical role in the development of AS. Unrestricted uptake of oxidized LDL (oxLDL) by macrophages leads to accumulation of lipid intracellularly and foam cell formation, which is a hallmark of early stages of AS. OxLDL uptake is mainly mediated by CD36, a scavenger receptor highly expressed on the macrophage surface. One major problem is that oxLDL leads to up-regulation of CD36 expression through a transcription factor PPARγ, resulting in a positive feedback mechanism to further enhance CD36-mediated oxLDL uptake. Defining the novel regulator of this process is the central goal of this multi-PI proposal. Recent published and preliminary studies showed that Pim1, a conserved serine/threonine kinase regulates CD36 transcription. In addition, genetic ablation of pim1 gene in macrophages resulted in a reduction in PPARγ pathway as well as the downstream targets involved in fatty acid metabolism and mitochondrial oxidative phosphorylation. We thus hypothesized that Pim1 kinase coordinates PPARγ activation/CD36 expression and mitochondrial functions to regulate fatty acid metabolism and immune activation in macrophages. Continuous stimulation of Pim1 kinase in macrophages contributes to pro-atherogenic phenotypes and AS. Specific aim 1 will determine the molecular mechanism by which Pim1 kinase in macrophages coordinates PPARγ activation/CD36 expression and mitochondrial function to modulate fatty acid metabolism. We will use a combination of genetically modified macrophages, biochemical, immunological and ex vivo cell metabolic studies to determine the mechanisms by which Pim1 kinase regulates fatty acid metabolism through the PPARγ/CD36 pathway; and to determine the mechanisms by which Pim1 kinase regulates mitochondria morphology through Drp-1 and define the impact on mitochondria fatty acid oxidation, oxidative phosphorylation and ROS production. Aim 2 will test the hypothesis that inactivating Pim1 kinase in vivo suppresses the development of AS. Using the genetic pim1 ablation model and minipump infusion of the Pim inhibitor AZD1208, we aim to test the hypothesis that Pim1 activity is indispensible for diet-induced AS in mice; and to test the hypothesis that pharmacologic inhibition of Pim1 suppresses PPARγ/CD36 pathway and reprograms macrophage mitochondria toward ROS production under atherogenic conditions; and test the hypothesis that Pim1 regulates bone marrow-monocyte-macrophage differentiation lineage under atherogenic conditions. By elucidating the molecular mechanisms by which Pim1 kinase coordinates fatty acid metabolism and mitochondrial functions to control macrophage activation under atherogenic conditions, we expect to gain crucial knowledge on novel lipid metabolism regulators and provide new treatment strategies against AS.