This renewal application builds upon our recent studies indicating that aldehyde dehydrogenase (ALDH) enzymes can be critical metabolic switches that link chromatin remodeling with gene expression in vascular and inflammatory cells, and that the dysregulation of specific ALDH isoforms is linked in the pathogenesis of pulmonary arterial hypertension (PAH). We use pulmonary arterial (PA) endothelial cells (EC), smooth muscle cells (SMC) and macrophages (M) and genetically modified mice to pursue our novel observations. Our Preliminary Data reveal increased mRNA and protein levels of ALDH1A3 in PA SMC from patients with PAH versus controls, which is required for their heightened proliferation. The mechanism is related to elevated nuclear production of acetyl CoA, acetylation of histones at enhancer marks (H3K27ac) and expression of genes associated with cell cycle progression.
In Aim 1, we use RNA Seq and ChIP Seq to probe the mechanism by which elevated ALDH1A3 increases cell cycle genes as well as other metabolic enzymes, i.e., PKM2, DLD and IDH1 and we study the impact of those enzymes on chromatin remodeling and gene expression. We investigate whether elevated ALDH1A3 could be regulated by mechanisms that are dependent a well as independent of BMPR2. Further experiments test whether deleting Aldh1a3 in SMC of genetically modified mice is sufficient to attenuate proliferation of PA SMC and pulmonary hypertension (PH) associated with chronic hypoxia. In PA EC, we found that a different ALDH isoform ALDH3A1, is increased in response to laminar flow. In contrast, ALDH2 a mitochondrial enzyme is elevated under static or disturbed flow conditions. Both ALDH isoforms are expected to preserve PA EC function through multiple metabolic pathways that affect gene expression.
Aim 2 will determine whether ALDH3A1 protects PA EC under laminar flow and ALDH2 under static conditions by relating their metabolomic profile to chromatin accessibility and gene expression. Localization of these ALDH isoforms will be studied in control and PAH lungs using 3-D vibratome imaging. Aldh3a1 or Aldh2 will be deleted in EC from genetically modified mice to determine whether this causes more severe PH following chronic hypoxia or 5-lipoxygenase mediated inflammation.
In Aim 3 we focus on ALDH1A2, an ALDH isoform implicated in polarization of M associated with resolution of inflammation, similar to the reported effect of BMPR2 ligands. We will determine whether deleting Aldh1a2 or Bmpr2 in interstitial M recruited to the lung in association with PH producing conditions, causes more severe disease related to persistent perivascular inflammation. Proteomics will be applied to analyze the secretome of these Aldh1a2 or Bmpr2 deleted M to better define the nature of the inflammatory response. The impact of the M with Aldh1a2 or Bmpr2 deleted on EC apoptosis or endothelial mesenchymal transition will also be investigated. Our studies are timely in addressing the significance of ADLH isoforms in PAH as small molecule agonists and antagonists of ALDH enzymes are being developed and tested in the clinic.
We link abnormal expression of members of the aldehyde dehydrogenase family of enzymes to changes in metabolism, chromatin and gene expression that adversely impact vascular and inflammatory cell function in pulmonary arterial hypertension. Our studies test the significance of our findings in human cells and tissues as well as in genetically modified mice.
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