LATS1/2-CD38 Metabolic Rewiring Links Senescence to Intraplaque Thrombosis

BACKGROUND: Atherothrombosis, which underlies most acute coronary syndromes and is driven by intraplaque thrombosis, preferentially occurs in regions of disturbed blood flow (d-flow). Although LATS1/2 (large tumor suppressor kinases 1 and 2) are known regulators of endothelial mechanotransduction, the mechanisms by which d-flow connects endothelial senescence, proliferation, and intraplaque thrombosis remain poorly understood. METHODS: We investigated endothelial cell (EC)-specific roles of LATS1/2 using inducible EC-specific knockout mice in a partial carotid ligation model. Spatial multiomics of human and mouse plaques was performed using imaging mass cytometry, COMET sequential immunofluorescence, and spatial metabolomics. RESULTS: -EC-specific knockout mice survived and developed spontaneous atherothrombotic plaques with neovascularization. Spatial proteomics revealed that LATS1/2 loss induced a senescence-associated stemness phenotype driven by CD38 upregulation. Spatial metabolomics showed sulfite and taurine accumulation, indicating SUOX (sulfite oxidase) deficiency. CD38 suppressed SUOX, demonstrated a switch into the reverse mode of mitochondrial complex V, increased succinate dehydrogenase activity, and promoted ATP consumption. Despite ATP depletion, glutamate metabolism and the citric acid cycle flux increased, sustaining EC proliferation under energetic stress. This senescence-associated stemness state promoted both proliferation and senescence, leading to fragile, leaky neovessels and intraplaque thrombotic lesions. Pharmacological CD38 inhibition attenuated these phenotypes. Similar EC states were observed in human plaques. CONCLUSIONS: Loss of LATS1/2 in ECs induces a CD38-associated senescence-associated stemness-like phenotype that promotes intraplaque thrombosis through mitochondrial metabolic reprogramming, including changes consistent with reverse-mode operation of mitochondrial complex V. These findings define a mechanistic link between disturbed flow, endothelial metabolic reprogramming, and intraplaque thrombosis and hemorrhage.

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Journal
Circulation Research
Published
2026-05-27
DOI
https://doi.org/10.1161/circresaha.125.327427
Primary Topic
Calcium signaling and nucleotide metabolism
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article
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article

LATS1/2-CD38 Metabolic Rewiring Links Senescence to Intraplaque Thrombosis

Vahid Afshar‐Kharghan, Jared K. Burks, Young Jin Gi, Jonghae Lee et al.
Circulation Research
Calcium signaling and nucleotide metabolism
article

LATS1/2-CD38 Metabolic Rewiring Links Senescence to Intraplaque Thrombosis

Vahid Afshar‐Kharghan, Jared K. Burks, Young Jin Gi, Jonghae Lee, Min Soon Cho, Nicolas L. Palaskas, John P. Cooke, Anita Deswal, Laurent Yvan‐Charvet, Nordin M.J. Hanssen, Dale J. Hamilton, Jun‐ichi Abe, Weiqing Chen, Paul S. Brookes, Philip L. Lorenzi, Iqbal Mahmud, Venkata Subrahman K Samanthapudi, Angie Zhang, Rajneesh Pathania, Masaki Imanishi, James F. Martin, Erin H. Seeley, Sivareddy Kotla, Guangyu Wang, Jung Hyun Kim, Hani Lee, Joerg Herrmann, Kyung Ae Ko, Keigi Fujiwara, Hernan G. Vasquez, Karla N. Mariscal-Reyes, Kay Carlene Tavares Samperio, Efstratios Koutroumpakis, Keri L. Schadler, Oanh Hoang, Luis Antonio Rivera, Eduardo N. Chini, Kelia C. Ostos-Mendoza, Haodong Xu, Lin Tan, Criag Morrell, Gilbert F. Mejia, Shengyu Li, Ying H. Shen, Nhat-Tu Le
article en

Abstract

BACKGROUND: Atherothrombosis, which underlies most acute coronary syndromes and is driven by intraplaque thrombosis, preferentially occurs in regions of disturbed blood flow (d-flow). Although LATS1/2 (large tumor suppressor kinases 1 and 2) are known regulators of endothelial mechanotransduction, the mechanisms by which d-flow connects endothelial senescence, proliferation, and intraplaque thrombosis remain poorly understood. METHODS: We investigated endothelial cell (EC)-specific roles of LATS1/2 using inducible EC-specific knockout mice in a partial carotid ligation model. Spatial multiomics of human and mouse plaques was performed using imaging mass cytometry, COMET sequential immunofluorescence, and spatial metabolomics. RESULTS: -EC-specific knockout mice survived and developed spontaneous atherothrombotic plaques with neovascularization. Spatial proteomics revealed that LATS1/2 loss induced a senescence-associated stemness phenotype driven by CD38 upregulation. Spatial metabolomics showed sulfite and taurine accumulation, indicating SUOX (sulfite oxidase) deficiency. CD38 suppressed SUOX, demonstrated a switch into the reverse mode of mitochondrial complex V, increased succinate dehydrogenase activity, and promoted ATP consumption. Despite ATP depletion, glutamate metabolism and the citric acid cycle flux increased, sustaining EC proliferation under energetic stress. This senescence-associated stemness state promoted both proliferation and senescence, leading to fragile, leaky neovessels and intraplaque thrombotic lesions. Pharmacological CD38 inhibition attenuated these phenotypes. Similar EC states were observed in human plaques. CONCLUSIONS: Loss of LATS1/2 in ECs induces a CD38-associated senescence-associated stemness-like phenotype that promotes intraplaque thrombosis through mitochondrial metabolic reprogramming, including changes consistent with reverse-mode operation of mitochondrial complex V. These findings define a mechanistic link between disturbed flow, endothelial metabolic reprogramming, and intraplaque thrombosis and hemorrhage.

Circulation Research
Houston Methodist (US), Michael E. DeBakey VA Medical Center (US), Mayo Clinic (US), The University of Texas MD Anderson Cancer Center (US), Inserm (FR), Rochester Institute of Technology (US), Baylor College of Medicine (US), Cornell University (US), Jacksonville College (US), Foundation Centrum '45 (NL), Amsterdam Neuroscience (NL), Methodist Hospital (US), BioEnergetics (United States) (US), Centre Méditerranéen de Médecine Moléculaire (FR), Mayo Clinic in Arizona (US), Norwegian Womens Public Health Association (NO), Mayo Clinic in Florida (US), Wake Forest University (US), University of Rochester (US), The University of Texas at Austin (US), Tecnológico de Monterrey (MX)
Good health and well-being
Openalex Percentile: Top 9%
Calcium signaling and nucleotide metabolism
DOISourceOpenAlex
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