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Circ. Res., May 27 2026, | https://doi.org/10.1161/CIRCRESAHA.125.327427 LATS1/2-CD38 Metabolic Rewiring Links Senescence to Intraplaque Thrombosis

Sivareddy Kotla ^{1 †}, Jonghae Lee ^{1 2 †}, Kyung Ae Ko ^{1 †}, Weiqing Chen ^{3 †}, Venkata Subrahmanya Kumar Samanthapudi ¹, Oanh Hoang ¹, Gilbert F Mejia ¹, Shengyu Li ³, Hani Lee ⁴, Aijun Zhang ^{5 6}, Min Soon Cho ⁴, Keri L Schadler ², Luis Antonio Rivera ¹, Masaki Imanishi ¹, Kay Carlene Tavares Samperio^{1 7}, Jung Hyun Kim^{1 8}, Kelia C Ostos-Mendoza^{1 8}, Karla N Mariscal-Reyes ^{1 7}, Anita Deswal ¹, John P Cooke ², Keigi Fujiwara ¹, Nicolas L Palaskas ¹, Efstratios Koutroumpakis ¹, Young Jin Gi ¹, Rajneesh Pathania ⁹, Criag Morrell ¹⁰, Philip L Lorenzi ¹¹, Lin Tan ¹¹, Iqbal Mahmud ¹¹, Nordin M J Hanssen ^{12 13}, Vahid Afshar-Kharghan ⁴, Dale J Hamilton ^{5 6}, Laurent Yvan-Charvet ¹⁴, Eduardo N Chini ¹⁵, Joerg Herrmann ¹⁶, Hernan G Vasquez¹⁷, Ying H Shen ¹⁷, James F Martin ¹⁸, Haodong Xu ¹⁹, Erin H Seeley ⁷, Jared K Burks ²⁰, Paul S Brookes²¹, Guangyu Wang ^{3 *}, Nhat-Tu Le ^{3 8 *}, Jun-Ichi Abe ^{1 *}

¹Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston. (S.K., J.L., K.A.K., V.S.K.S., O.H., G.F.M., L.A.R., M.I., K.C.T.S., J.H.K., K.C.O.-M., K.N.M.-R., A.D., K.F., N.L.P., E.K., Y.J.G., J.-I.A.).
²Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston. (J.L., K.L.S., J.P.C.).
³Department of Cardiovascular Sciences, Houston Methodist Research Institute, TX (W.C., S.L., G.W., N.-T.L.).
⁴Section of Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston (H.L., M.S.C., V.A.-K.).
⁵Center for Bioenergetics, Houston Methodist Research Institute, TX (A.Z., D.J.H.).
⁶Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, TX (A.Z., D.J.H.).
⁷Department of Chemistry, the University of Texas at Austin (K.C.T.S., K.N.M.-R., E.H.S.).
⁸Instituto Tecnológico y de Estudios Superiores de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo León, México (J.H.K., K.C.O.-M., N.-T.L.).
⁹Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston. (R.P.).
¹⁰Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester, NY. (C.M.).
¹¹Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston. (P.L.L., L.T., I.M.).
¹²Department of (Experimental) Vascular and Internal Medicine, Amsterdam UMC, the Netherlands (N.M.J.H.).
¹³Diabeter Centrum Amsterdam, the Netherlands (N.M.J.H.).
¹⁴Institut National de la Santé et de la Recherche Médicale (Inserm) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Fédération Hospitalo-Universitaire (FHU) Oncoage, IHU Respiratory Health, Environment and Ageing (RespirERA), Nice, France (L.Y.-C.).
¹⁵Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL (E.N.C.).
¹⁶Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (J.H.).
¹⁷Michael E. Debakey Department of Surgery, Baylor College of Medicine, Houston, TX (H.G.V., Y.H.S.).
¹⁸Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX (J.F.M.).
¹⁹Department of Anatomic Pathology, Wake Forest University School of Medicine, Winston-Salem, NC (H.X.).
²⁰Division of Center Medicine, Department of Leukemia (J.K.B.), The University of Texas MD Anderson Cancer Center, Houston.
²¹Department of Anesthesiology and Perioperative Medicine, University of Rochester, NY. (P.S.B.).

^†These authors contributed equally

^*Corresponding authors: correspondence to Guangyu Wang, Nhat-Tu Le or Jun-Ichi Abe

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:
Tamoxifen-induced deletion of both Lats1 and Lats2 (homozygous) in ECs caused fatal edema and increased vascular permeability. In contrast, Lats1^het(±)/Lats2 ^{homo(−/−)}-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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