Deepesh Pandey - Research & Publications

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Research Interests

The main scientific focus of my laboratory is the epigenetic mechanisms by which Histone Deacetylase 2 (HDAC2) maintains vascular endothelial function, and to harness systems-level insights to identify additional master regulatory genes that are important for endothelial health and atherogenesis prevention. We are currently investigating the mechanisms underlying endothelial cell dysfunction in atherosclerosis by delineating connections between HDAC2 and genes critical for endothelial function such as mitochondrial Arginase 2.

In another exciting new project, we have capitalized on findings from the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). In HGPS an internally deleted form of the mechanoresponsive nuclear scaffold protein lamin A is permanently farnesylated, and leads to the early aging phenotypes characteristic of the disease, the most prominent of which is highly aggressive, early onset atherosclerosis. HGPS is a genetic disorder caused by mutation in the LMNA gene that encodes the mechanoresponsive nuclear scaffold protein lamin A, critical in maintaining normal nuclear morphology and responding to mechanical stresses from the extracellular environment. Our hypothesis is that if farnesylated full-length prelamin A, a normally transient biosynthetic intermediate in healthy individuals, were to accumulate during physiological aging (for instance, due to even slightly decreased expression or activity of the ZMPSTE24 protease) it could, like progerin (in HGPS syndrome), drive geriatric vascular dysfunction and atherosclerosis in the general population.

Our multi-level studies focus on vasculopathy in the development of pulmonary hypertension, and atherogenesis, and range from transcriptional regulation, to the biochemistry of post-translational modification (sumoylation, neddylation, and ubiquitination) and proteasomal degradation.

Research Projects

Proper processing of nuclear scaffold protein lamin A by endothelial ZMPSTE24 plays a mechanoregulatory role in protection from vascular pathology
Lamin A is thought to play a critical role in mechanosensing through its interaction via the LINC complex that spans nuclear envelope and interacts with cytoskeletal filaments, allowing cells to cope with mechanical forces coming from the outside. The aorta is subject to high levels of hemodynamic mechanical stress and is one of the tissues in which lamin A levels are highest, presumably helping to handle the mechanical shear stress of blood flow. In this project, we will test endothelial cell function by inhibiting lamin A processing, but in an experimental setting that better mimics the mechanical stress experienced by vascular endothelial cells in vivo than do static cells in culture. KLF2 is a transcription factor that is induced by fluid shear stress. We have shown that increased expression of KLF2 in quiescent endothelial cells co-ordinately upregulates ZMPSTE24 and LMNA, suggesting that properly processed prelamin A may be required to respond to the mechanical force induced by shear stress. Here we will conduct experiments using a microfluidic platform to culture cells that can accommodate differing flow conditions and generate defined levels of shear stress.
Mechanisms of SARS-CoV2-mediated injury in the lung microcirculation
Endothelial dysfunction is implicated in the thrombotic events reported in COVID-19 patients, but underlying molecular mechanisms are unknown. Circulating levels of the coagulation cascade activator PAI-1 are substantially higher in COVID-19 patients with severe respiratory dysfunction than in patients with bacterial-sepsis and ARDS. Therefore, we tested the hypotheses that the SARS-CoV-2 causes lung microvascular endothelial dysfunction and thrombosis by stimulating production of abnormally high levels of anti-fibrinolytic endothelial plasminogen activator inhibitor (PAI-1) and that these effects are mitigated by ZMPSTE24-mediated cleavage and shedding of the ACE2 receptor ectodomain. Our hypotheses are based on our findings in endothelial cells, including the additional insights that ZMPSTE24 function declines with aging and with exposure to agents that cause lung endothelial injury such as cigarette smoke extract. Notably, aging and history of cigarette smoking are issues that have been found to be predictive of more severe lung disease in patients infected with COVID-19. Additionally, previous work by others indicates that ZMPSTE24 is critical for antiviral function of interferon-induced transmembrane proteins (IFITMs) against enveloped RNA viruses including strains of coronaviruses that have caused previous epidemics such as SARS-CoV and MERS-CoV.
Transcriptional and epigenetic regulation of endothelial cell function
Epigenetic pathways that regulate endothelial cell responses to oxidative injury are poorly understood. We investigated transcriptional and epigenetic regulation of genes that are important for endothelial cell function in response to stimuli that causes oxidative injury such as oxidized low-density lipoprotein, hypoxia and cigarette smoke extract. Notably, using transgenic mice model with targeted overexpression of HDAC2 in endothelium and endothelial cell culture, we have demonstrated protective role of HDAC2 in endothelial function and atherogenesis. In another area of research, we are addressing the gap of knowledge in the pathobiology of pulmonary hypertension (PH): pulmonary microvascular endothelial dysfunction. Specifically, we are testing the role of a putative pathogenic pathway in PH that involves posttranslational modification of transcription factor Kruppel-Like Factor 15 (KLF15) by SUMO-1 and uncoupling of eNOS in the pulmonary microvasculature.

Spotlight Publications

Han M, Pandey D. ZMPSTE24 Regulates SARS-CoV-2 Spike Protein-enhanced Expression of Endothelial Plasminogen Activator Inhibitor-1. American Journal of Respiratory Cell and Molecular Biology; 65(3):300-308, 2021 (Accompanying editorial: Khan, SS American Journal of Respiratory Cell and Molecular Biology 2021, 65(3):238-240).

Pandey D, Bhunia A, Oh YJ, Chang F, Bergman Y, Hyung JK, Serbo J, Boronina TN, Cole RN, Eyk JV, Remaley AT, Berkowitz D*, Romer L*. OxLDL Triggers Retrograde Translocation of Arginase 2 in Aortic Endothelial Cells via ROCK and Mitochondrial Processing Peptidase. Circulation Research; 115(4): 450-459, 2014 (Accompanying editorial: Touyz, RM Circ Res 2014, 115:412-414).

Recent Publications

Han M, Pandey D. ZMPSTE24 Regulates SARS-CoV-2 Spike Protein-enhanced Expression of Endothelial Plasminogen Activator Inhibitor-1. American Journal of Respiratory Cell and Molecular Biology, 2021 (In press).

Pandey D*, Nomura Y, Rossberg MC, Hori D, Bhatta A, Keceli G, Leucker T, Santhanam L, Shimoda L, Berkowitz D, Romer L. Hypoxia Triggers SENP1 Modulation of Kruppel-Like Factor 15 and Transcriptional Regulation of Arginase 2 in Pulmonary Endothelium. Arteriosclerosis, Thrombosis, and Vascular Biology; 38(4):913-926, 2018 (* Corresponding author).

Pandey D, Hori D, Kim JH, Bergman Y, Berkowitz DE*, Romer LH*. NEDDylation Promotes Endothelial Dysfunction: A Role for HDAC2. J Mol Cellular Cardiology; 81:18-22, 2015.

Pandey D, Sikka G, Bergman Y, Kim JH, Ryoo S, Romer L*, Berkowitz D*. Transcriptional Regulation of Endothelial Arginase 2 by HDAC2. Arteriosclerosis, Thrombosis, Vascular Biology; 34(7):1556-1566, 2014.

Sikka G, Hussmann GP, Pandey D, Cao S, Hori D, Park JT, Steppan J, Kim JH, Barodka V, Myers AC, Santhanam L, Nyhan D, Halushka MK, Koehler RC, Snyder SH, Shimoda LA, Berkowitz DE. Melanopsin mediates light-dependent relaxation in blood vessels. PNAS; 111(50):17977-82, 2014.

Pandey D, Patel A, Patel V, Chen F, Qian J, Wang Y, Barman SA, Venema RC, Stepp DW, Rudic RD, Fulton DJ. Expression and functional relevance of NADPH Oxidase 5 (Nox5) and its splice variants in human blood vessels. Am J Physiol-Heart Circulatory Physiology; 302(10): H1919-1928, 2012.

Pandey D, Fulton D. Calcium/Calmodulin-dependent Kinase II (CAMKII) mediates the Phosphorylation and Activation of NADPH Oxidase 5. Molecular Pharmacology; 80(3): 407-415, 2011.

Pandey D, Chen F, Patel A, Dimitropoulou C, Wang CY, Rudic RD, Stepp DW, Fulton D. SUMO-1 Negatively Regulates Reactive Oxygen Species Production from NADPH Oxidases. Arteriosclerosis Thrombosis Vascular Biology; 31(7): 1634-1642, 2011.

Pandey D, Fulton D. Molecular Regulation of NADPH Oxidase 5 (Nox5) via the MAPK kinase pathways. Am J Physiol-Heart Circulatory Physiology; 300(4): H1336-1344, 2011.

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