Document text
Principal Investigator: John YJ Shyy
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $652,773
Funding agency: National Heart Lung and Blood Institute
Project Summary
Vascular endothelial cell (EC) metabolism is essential for functional endothelium, and maladapted energy use
severely affects EC health. AMP-activated protein kinase (AMPK) is a key regulator of cellular energy status and
homeostatic function. Our preliminary studies showed that energy stress results in spatially defined AMPK
activity at cellular organelles, which indicates that AMPK activity is compartmentalized in the cell. An emerging
AMPK substrate in the vascular endothelium is angiotensin-converting enzyme 2 (ACE2), and we have found
that the AMPK–ACE2 axis enhances EC function and is atheroprotective. SARS-CoV viruses invade the host
cells by binding the viral spike protein (S protein) to ACE2, which leads to decreased membrane ACE2 levels,
increased extracellular soluble ACE2, and increased glycolysis, thus resulting in host cell damage. In preliminary
studies, we have also found that the SARS-CoV-2 S protein deactivates the AMPK–ACE2 axis and impairs EC
function in vitro and in vivo. This impairment is likely to constitute a risk factor for the long-term effects of SARS-
CoV-2 infection or post-acute sequelae of SARS-CoV-2 infection (PASC). These preliminary findings lead to the
hypothesis that EC homeostasis is maintained via the spatiotemporal regulation of the AMPK–ACE2 axis. In
contrast, S protein entry disrupts cellular energetics in ECs, leading to dysregulated AMPK and the ensuing
ACE2 hypo-phosphorylation, which critically contributes to the COVID-19–associated EC dysfunction and PASC.
The three specific aims proposed to test this novel hypothesis are as follows: Aim 1. To investigate the
spatiotemporal regulation of AMPK in ECs under physiological [e.g., pulsatile shear stress (PS)],
pharmacological (e.g., metformin), and pathophysiological (e.g., S protein) conditions; Aim 2. To decipher the
mechanisms by which physiological, pharmacological, and pathophysiological stimuli modulate the AMPK–
ACE2 axis in ECs; Aim 3. To investigate the role of impaired AMPK–ACE2 axis in S protein-accelerated
atherosclerosis in the context of PASC. In the proposed research, we will use live cell imaging, in vitro EC biology,
and in vivo animal models to determine the role of the AMPK–ACE2 axis in endothelial health and disease.
These findings will result in otherwise missing insights into the pathophysiology of PASC, which will continue to
be a long-term consequence of SARS-CoV-2 infection.
Terms: <(hydroxymethylglutaryl-CoA reductase (NADPH)) kinase><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><5'-AMP-activated protein kinase><ACE2><AMP-activated kinase><AMP-activated protein kinase><AMPK enzyme><ATP-protein phosphotransferase><Acceleration><Affect><AngII><Angiotensin II><Angiotensins><Animal Model><Animal Models and Related Studies><Arterial Lines><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Autoregulation><Binding><Biology><COVID-19><COVID-19 S protein><COVID-19 infection><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 virus><CV-19><Cardiac Diseases><Cardiac Disorders><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Mechanotransduction><Cellular Metabolic Process><Cellular Physiology><Cellular Process><Cellular biology><Cellular injury><CoV-2><CoV2><Coronavirus Infectious Disease 2019><Cues><Dimethylbiguanidine><Dimethylguanylguanidine><Disease><Disorder><Dysfunction><Endothelial Cells><Endothelium><Functional disorder><Glycolysis><Goals><HMG CoA reductase (NADPH) kinase><HMG CoA reductase kinase><HMG coenzyme A reductase (NADPH) kinase><Health><Heart Diseases><Homeostasis><Impairment><In Vitro><Inflammation><Intra-Arterial Lines><Intracellular Communication and Signaling><Invaded><Kinase Family Gene><Kinases><Lead><Link><Long-Term Effects><Longterm Effects><Mechanical Signal Transduction><Mechanosensory Transduction><Membrane><Metformin><Molecular><Molecular Interaction><Mutant Strains Mice><N,N-dimethyl-imidodicarbonimidic diamide><Organelles><Oxidation-Reduction><PASC><Pb element><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Play><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Proliferating><Protein Kinase><Protein Phosphorylation><Proteins><Redox><Regulation><Renin-Angiotensin-Aldosterone System><Reporter><Research><Risk Factors><Role><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 infection><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 infection><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Stimulus><Stress><Subcellular Process><Testing><Transphosphorylases><Up-Regulation><Upregulation><Vascular Endothelial Cell><Vascular Endothelium><Vasodilatation><Vasodilation><Vasorelaxation><Viral><Virus><Wuhan coronavirus><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><angiogenesis><angiotensin converting enzyme 2><angiotensin converting enzyme II><arm><atheromatosis><atheroprotection><atheroprotective><atherosclerotic disease><atherosclerotic vascular disease><biological signal transduction><cardiovascular disorder><cardiovascular health><cell biology><cell damage><cell injury><cell metabolism><cell type><cellular damage><cellular metabaolism><chronic COVID-19 sequelae><chronic effect of COVID-19><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 infection><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 virus><coronavirus infectious disease-19><damage to cells><energy balance><extracellular><functional outcomes><glycogen synthase a kinase><hCoV19><heart disorder><heavy metal Pb><heavy metal lead><hydroxyalkyl protein kinase><hydroxymethylglutaryl-CoA-reductase kinase><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><injury to cells><innovate><innovation><innovative><insight><interest><live cell image><live cell imaging><live cellular image><live cellular imaging><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long term consequences of COVID-19><long term consequences of SARS-CoV-2 infection><long term consequences of coronavirus disease-19><long term effects of COVID-19><long term health consequences of COVID-19><long term health consequences of SARS-CoV2 infection><long term impact of COVID-19><long term impact of SARS-CoV-2 infection><long-term consequence of severe acute respiratory distress syndrome-cov-2 infection><long-term effects of coronavirus disease-19><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><longterm consequences of COVID-19><longterm consequences of SARS-CoV-2 infection><longterm effects of COVID-19><longterm health consequences of COVID-19><longterm health consequences of SARS-CoV2 infection><longterm impact of COVID-19><longterm impact of SARS-CoV-2 infection><mechanosensing><mechanotransduction><membrane structure><model of animal><mouse model><mouse mutant><murine model><nCoV2><novel><oxidation reduction reaction><pathophysiology><pharmacologic><phosphorylase b kinase kinase><post COVID-19 sequelae><post acute sequelae following COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><severe acute respiratory syndrome-CoV><shear stress><social role><spatiotemporal><spike proteins on SARS-CoV-2><tool><upstream kinase>