Myeloid-Specific JAK2 Contributes to Inflammation and Salt Sensitivity of Blood Pressure.

Janus kinase 2 STAT3 transcription factor Smad proteins blood pressure hypertension

Journal

Circulation research
ISSN: 1524-4571
Titre abrégé: Circ Res
Pays: United States
ID NLM: 0047103

Informations de publication

Date de publication:
12 Sep 2024
Historique:
medline: 12 9 2024
pubmed: 12 9 2024
entrez: 12 9 2024
Statut: aheadofprint

Résumé

Salt sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen-presenting cells (APCs), resulting in high blood pressure, but the mechanisms are unknown. Here, we hypothesized that APC-specific JAK2 (Janus kinase 2) through STAT3 (signal transducer and activator of transcription 3) and SMAD3 (small mothers against decapentaplegic homolog 3) contributes to SSBP. We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP. We also used a myeloid cell-specific CD11c We found that high salt treatment upregulates gene expression of the JAK/STAT/SMAD pathway while downregulating inhibitors of this pathway, such as suppression of cytokine signaling and cytokine-inducible SH2, in human monocytes. Expression of the JAK2 pathway genes mirrored changes in blood pressure after salt loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11c Our findings reveal the APC JAK2 signaling pathway as a potential target for the diagnosis and treatment of SSBP in humans.

Sections du résumé

BACKGROUND UNASSIGNED
Salt sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen-presenting cells (APCs), resulting in high blood pressure, but the mechanisms are unknown. Here, we hypothesized that APC-specific JAK2 (Janus kinase 2) through STAT3 (signal transducer and activator of transcription 3) and SMAD3 (small mothers against decapentaplegic homolog 3) contributes to SSBP.
METHOD UNASSIGNED
We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP. We also used a myeloid cell-specific CD11c
RESULTS UNASSIGNED
We found that high salt treatment upregulates gene expression of the JAK/STAT/SMAD pathway while downregulating inhibitors of this pathway, such as suppression of cytokine signaling and cytokine-inducible SH2, in human monocytes. Expression of the JAK2 pathway genes mirrored changes in blood pressure after salt loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11c
CONCLUSIONS UNASSIGNED
Our findings reveal the APC JAK2 signaling pathway as a potential target for the diagnosis and treatment of SSBP in humans.

Identifiants

DOI: 10.1161/CIRCRESAHA.124.323595 PMID: 39263750
pubmed: 39263750
doi: 10.1161/CIRCRESAHA.124.323595
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Auteurs

Mohammad Saleem (M)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
ORCID: 0000-0001-8091-8361

Luul A Aden (LA)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
ORCID: 0000-0002-9483-860X

Ashley Pitzer Mutchler (AP)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).

Chitra Basu (C)

Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN. (C.B., E.R.G.).
Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN. (C.B., A.K.H.).

Lale A Ertuglu (LA)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
ORCID: 0000-0002-6318-4199

Quanhu Sheng (Q)

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN. (Q.S.).
ORCID: 0000-0001-8951-9295

Niki Penner (N)

Division of Allergy, Pulmonary, and Critical Care Medicine (N.P., A.R.H.).

Anna R Hemnes (AR)

Division of Allergy, Pulmonary, and Critical Care Medicine (N.P., A.R.H.).
ORCID: 0000-0002-2755-5845

Jennifer H Park (JH)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).

Jeanne A Ishimwe (JA)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
ORCID: 0000-0002-5479-7284

Cheryl L Laffer (CL)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
ORCID: 0000-0002-6453-6010

Fernando Elijovich (F)

ORCID: 0000-0002-2511-056X

Celestine N Wanjalla (CN)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
ORCID: 0000-0001-9159-5414

Nestor de la Visitacion (N)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
ORCID: 0000-0001-7229-9601

Paul D Kastner (PD)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
ORCID: 0009-0003-2074-0380

Claude F Albritton (CF)

School of Graduate Studies, Meharry Medical College, Nashville, TN (C.F.A.).
ORCID: 0000-0002-6891-8737

Taseer Ahmad (T)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
Department of Pharmacology, College of Pharmacy, University of Sargodha, Punjab, Pakistan (T.A.).
ORCID: 0000-0003-4545-9598

Alexandria P Haynes (AP)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
ORCID: 0009-0004-3723-0325

Justin Yu (J)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
ORCID: 0009-0004-6400-5633

Meghan K Graber (MK)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
ORCID: 0009-0007-4096-4751

Sharia Yasmin (S)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
ORCID: 0000-0002-8452-405X

Kay-Uwe Wagner (KU)

Wayne State University, Department of Oncology and Tumor Biology Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI (K.-U.W.).
ORCID: 0000-0002-5081-0226

Peter P Sayeski (PP)

Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville (P.P.S.).

Antonis K Hatzopoulos (AK)

Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN. (C.B., A.K.H.).

Eric R Gamazon (ER)

Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN. (C.B., E.R.G.).

Alexander G Bick (AG)

Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN. (A.G.B.).
ORCID: 0000-0001-5824-9595

Thomas R Kleyman (TR)

Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, PA (T.R.K.).
ORCID: 0000-0002-2413-5415

Annet Kirabo (A)

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN (M.S., L.A.A., A.P.M., L.A.E., J.H.P., J.A.I., C.L.L., C.N.W., N.d.l.V., P.D.K., T.A., A.P.H., J.Y., M.K.G., S.Y., A.K.).
Vanderbilt Center for Immunobiology (A.K.).
Vanderbilt Institute for Infection, Immunology and Inflammation (A.K.).
Vanderbilt Institute for Global Health (A.K.).
ORCID: 0000-0001-8580-9359

Classifications MeSH