Premature aging disorders, metabolites, and atherosclerosis

Project Summary/Abstract
Premature senescence-triggered vascular diseases (PmSVD) induced by ionizing radiation (IR), as well
as Hutchinson-Gilford progeria syndrome (HGPS), are notably characterized by accelerating processes
of atherosclerosis (AthS) and coronary artery disease (CAD). Although endothelial dysfunction in PmSVDs is well
known, there is a paucity of available treatments to prevent PmSVD-induced CAD; hence, there is an urgent need to
fill this gap. Persistent senescence-associated secretory phenotype (PISP), provoked by TL dysfunction, plays a
central role in cancer recurrence and resistance, but its regulatory mechanisms and contribution to AthS remain
unknown. Our long-term goal is to determine the molecular mechanisms by which PmSVD induces PISP in
endothelial cells (ECs) and CAD. PmSVD significantly up-regulated TOP2β degradation via PKCζ activation. The
depletion of EC TOP2β instigated PARP activation and PISP; it also accelerated AthS. We showed the critical
role of mtROS in PKCζ activation, which is one of the initial steps for the Mt-nucleus feedback loop. Of note, the
crucial role of mtROS in both IR and HGPS has been well established. Lastly, by performing IC-MS analysis in both
IR and HGPS ECs, we also found that the following 3 metabolite-related pathways were regulated in IR and HGPS
ECs in common: 1) nucleotide sugars-glycosaminoglycans (GAGs) and sulfate, 2) glutamate, and 3) NAD+-
hydrogen sulfide (H2S). Although the contribution of all 3 metabolites pathways to CAD and aging has been
suggested, the exact role and mechanical insights in regulating PmSVD remain largely unknown. We propose the
novel hypothesis that PmSVD-induced mtROS activates the PKCζ-TOP2β module, followed by TOP2β
degradation, and instigates TL DNA damage. TL DNA damage promotes PARP activation, which induces mt
dysfunction and forms an mt-nucleus feedback loop, resulting in persistent metabolites changes, including
nucleotide sugars and NAD+-H2S pathways, causing PISP and CAD. We will test our hypothesis by pursuing the
following 3 specific aims: In Aim 1, we will determine the role and regulatory mechanisms of the following 3 common
metabolites-related pathways in PmSVD in vitro; 1) nucleotide sugars-GAGs and sulfate, 2) glutamate, 3) NAD+-
H2S. in Aim 2, we will characterize the role of PKCζ-TOP2β module and PARP1 in PmSVD-mediated metabolites
changes and mt dysfunction in vitro. In Aim 3, we will determine the role of the PKCζ-TOP2β module and
subsequent PARP activation in PmSVD-induced coronary AthS (CAthS) in vivo. The proposed work is
expected to establish the roles of PKCζ-TOP2β and PARP as the hub molecules in regulating PmSVD-induced
metabolite changes and PISP. The approach is innovative because we will use the new technologies of iPSC, ion
chromatography-mass spectrometry (IC-MS), machine learning, imaging mass cytometry, and a novel mouse
CAthS model. The proposed research should positively impact PmSVD by leading to a novel approach to
inhibiting PISP.

Grant Number: 5R01HL163857-03
NIH Institute/Center: NIH
Principal Investigator: Jun-Ichi Abe