LATS1/2-CD38 Metabolic Rewiring Links Senescence to Intraplaque Thrombosis.
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Kotla Sivareddy, Lee Jonghae, Ko Kyung Ae, Chen Weiqing, Samanthapudi Venkata Subrahmanya Kumar, Hoang Oanh, Mejia Gilbert F, Li Shengyu, Lee Hani, Zhang Aijun, Cho Min Soon, Schadler Keri L, Rivera Luis Antonio, Imanishi Masaki, Tavares Samperio Kay Carlene, Kim Jung Hyun, Ostos-Mendoza Kelia C, Mariscal-Reyes Karla N, Deswal Anita, Cooke John P, Fujiwara Keigi, Palaskas Nicolas L, Koutroumpakis Efstratios, Gi Young Jin, Pathania Rajneesh, Morrell Craig, Lorenzi Philip L, Tan Lin, Mahmud Iqbal, Hanssen Nordin M J, Afshar-Kharghan Vahid, Hamilton Dale J, Yvan-Charvet Laurent, Chini Eduardo N, Herrmann Joerg, Vasquez Hernan G, Shen Ying H, Martin James F, Xu Haodong, Seeley Erin H, Burks Jared K, Brookes Paul S, Wang Guangyu, Le Nhat-Tu, Abe Jun-Ichi
Аннотация
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, Lats1het(±)/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.