{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T03:53:17Z","timestamp":1794109997181,"version":"4.8.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,6,19]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Endothelial dysfunction is an early event in atherosclerosis development and is centrally linked with insufficient endothelial NO production. However, chronically increased NO levels, including NO from other cellular sources, may induce endothelial dysfunction. Here, we studied how chronically elevated NO production from erythrocytes, achieved by genetic deletion of ARG1 (arginase-1), impacts smooth muscle cell (SMC) lipid accumulation and atherosclerosis progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Primary aortic SMCs from mice lacking ARG1 in red blood cell (RBC.ARG1-knockout [KO]) were subjected to RNA-sequencing, lipidomic, metabolic, and molecular analyses; atherosclerosis burden was quantified en face and at the aortic root.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Increased lipid droplet formation in SMCs from RBC.ARG1-KO mice was observed using brightfield and electron microscopy and confirmed by Oil Red O and boron-dipyrromethene lipid dye staining. RNA sequencing revealed the simultaneous overexpression of genes regulating lipid uptake (\n                      <jats:italic toggle=\"yes\">Cd36<\/jats:italic>\n                      ), catabolism (\n                      <jats:italic toggle=\"yes\">Cpt1a<\/jats:italic>\n                      ), and de novo lipogenesis (\n                      <jats:italic toggle=\"yes\">Acaca<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">Fasn<\/jats:italic>\n                      [\n                      <jats:italic toggle=\"yes\">Fatty acid synthase<\/jats:italic>\n                      ]) in RBC.ARG1-KO SMCs, and inhibiting fatty acid translocase (CD36), ACC (acetyl-CoA [coenzyme A] carboxylase), or fatty acid synthase prevented the lipid accumulation in RBC.ARG1-KO SMCs. Increased expression of CD36 downstream of NO and overactivated sGC (soluble guanylyl cyclase)-cyclic guanosine monophosphate signaling was identified as a mediator of increased lipid uptake in RBC.ARG1-KO SMCs. Loss of PDE (phosphodiesterase) 2A, coupling cyclic guanosine monophosphate with cyclic adenosine monophosphate and PKA (protein kinase A) activation, was also observed, resulting in AMPK (5\u2019 AMP-activated protein kinase) inhibition, thus unlocking acetyl-CoA carboxylase, catalyzing the rate-limiting step in fatty acid synthesis. Inhibiting PDE2A recapitulated the RBC.ARG1-KO SMC phenotype, while inhibiting PKA or ATP generation from cyclic adenosine monophosphate abrogated the lipid droplet accumulation in RBC.ARG1-KO SMCs. Increased Oil Red O-positive aortic atherosclerosis burden in hypercholesterolemic apolipoprotein E\u2013deficient RBC.ARG1-KO mice was confirmed by histology and elevated levels of polyunsaturated long-chain cholesterol esters in aortic atheroma by mass spectrometry lipidomics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Our findings show the importance of erythrocyte-derived NO for metabolically reprogramming SMCs toward increased fatty acid uptake and lipogenesis, and identify PDE2A as a molecular switch linking chronically activated NO signaling with lipid accumulation and atheroma progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.327866","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T09:00:16Z","timestamp":1777626016000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Chronic Erythrocyte NO Production Accelerates Atherosclerosis by Increasing SMC De Novo Lipogenesis"],"prefix":"10.1161","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4948-1494","authenticated-orcid":true,"suffix":"(\u5b59\u5317\u8fb0)","given":"Beichen","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Cardiology (B.S., R.G., I.G., M.L.B., K.M., L.R., P.G., P.L., K.S.), University Medical Center, Mainz, Germany."},{"name":"Deutsches Zentrum f\u00fcr Herz-Kreislauf-Forschung e.V., partner site Rhine-Main (B.S., R.G., F.G., I.G., M.L.B., K.M., L.R., P.G., W.R., C.R., I.F., L.B., P.L., K.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1284-9338","authenticated-orcid":true,"given":"Rajinikanth","family":"Gogiraju","sequence":"additional","affiliation":[{"name":"Department of Cardiology (B.S., R.G., I.G., M.L.B., K.M., L.R., P.G., P.L., K.S.), University Medical Center, Mainz, Germany."},{"name":"Deutsches Zentrum f\u00fcr Herz-Kreislauf-Forschung e.V., partner site Rhine-Main (B.S., R.G., F.G., I.G., M.L.B., K.M., L.R., P.G., W.R., C.R., I.F., L.B., P.L., K.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8780-8528","authenticated-orcid":true,"given":"Franziska","family":"Greulich","sequence":"additional","affiliation":[{"name":"Institute for Metabolic Programming, TUM School of Life Sciences, ZIEL-Institute for Food &amp; Health, Technische Universit\u00e4t M\u00fcnchen, Freising, Germany (F.G.)."},{"name":"Deutsches Zentrum f\u00fcr Herz-Kreislauf-Forschung e.V., partner site Rhine-Main (B.S., R.G., F.G., I.G., M.L.B., K.M., L.R., P.G., W.R., C.R., I.F., L.B., P.L., K.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0312-157X","authenticated-orcid":true,"given":"Frank","family":"Kumi","sequence":"additional","affiliation":[{"name":"Clinical Lipidomics Unit, Institute of Physiological Chemistry, Johannes Gutenberg University (F.K., L.B.), University Medical Center, Mainz, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4832-8757","authenticated-orcid":true,"given":"Iman","family":"Ghasemi","sequence":"additional","affiliation":[{"name":"Department of Cardiology (B.S., R.G., I.G., M.L.B., K.M., L.R., P.G., P.L., K.S.), University Medical Center, Mainz, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5577-0238","authenticated-orcid":true,"given":"Magdalena L.","family":"Bochenek","sequence":"additional","affiliation":[{"name":"Department of Cardiology (B.S., R.G., I.G., M.L.B., K.M., L.R., P.G., P.L., K.S.), University Medical Center, Mainz, Germany."},{"name":"Center for Thrombosis and Hemostasis (M.L.B., S. 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