cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice

Maria Shvedova; Maxim M Litvak; Jesse D Roberts, Jr; Dai Fukumura; Tomoaki Suzuki; İkbal Şencan; Ge Li; Paula Reventun; Emmanuel S Buys; Hyung-Hwan Kim; Sava Sakadžić; Cenk Ayata; Paul L Huang; Robert Feil; Dmitriy N Atochin

doi:10.1177/0271678X19870583

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cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice

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cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice

Maria Shvedova, Maxim M Litvak, Jesse D Roberts, Jr, Dai Fukumura, Tomoaki Suzuki, İkbal Şencan, Ge Li, Paula Reventun, Emmanuel S Buys, Hyung-Hwan Kim, …

Journal of cerebral blood flow and metabolism, Vol.39(12), pp.2379-2391

01/12/2019

DOI: https://doi.org/10.1177/0271678X19870583

PMID: 31423931

Résumé

Animals

Cerebral Infarction - enzymology

Cerebral Infarction - genetics

Cerebral Infarction - pathology

Cyclic GMP-Dependent Protein Kinase Type I - genetics

Cyclic GMP-Dependent Protein Kinase Type I - metabolism

Female

Male

Mice

Mice, Knockout

Muscle, Smooth, Vascular - enzymology

Muscle, Smooth, Vascular - pathology

Myocytes, Smooth Muscle - enzymology

Myocytes, Smooth Muscle - pathology

Reperfusion Injury - enzymology

Reperfusion Injury - genetics

Reperfusion Injury - pathology

Stroke - enzymology

Stroke - genetics

Stroke - pathology

Recent works highlight the therapeutic potential of targeting cyclic guanosine monophosphate (cGMP)-dependent pathways in the context of brain ischemia/reperfusion injury (IRI). Although cGMP-dependent protein kinase I (cGKI) has emerged as a key mediator of the protective effects of nitric oxide (NO) and cGMP, the mechanisms by which cGKI attenuates IRI remain poorly understood. We used a novel, conditional cGKI knockout mouse model to study its role in cerebral IRI. We assessed neurological deficit, infarct volume, and cerebral perfusion in tamoxifen-inducible vascular smooth muscle cell-specific cGKI knockout mice and control animals. Stroke experiments revealed greater cerebral infarct volume in smooth muscle cell specific cGKI knockout mice (males: 96 ± 16 mm ; females: 93 ± 12 mm , mean±SD) than in all control groups: wild type (males: 66 ± 19; females: 64 ± 14), cGKI control (males: 65 ± 18; females: 62 ± 14), cGKI control with tamoxifen (males: 70 ± 8; females: 68 ± 10). Our results identify, for the first time, a protective role of cGKI in vascular smooth muscle cells during ischemic stroke injury. Moreover, this protective effect of cGKI was found to be independent of gender and was mediated via improved reperfusion. These results suggest that cGKI in vascular smooth muscle cells should be targeted by therapies designed to protect brain tissue against ischemic stroke.

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Détails

Titre: cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice
Créateurs - sans rôle: Maria Shvedova - Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA
Maxim M Litvak - Tomsk Polytechnic University, RASA Center, Tomsk, Russian Federation
Jesse D Roberts, Jr - Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA
Dai Fukumura - Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital, Boston, MA, USA
Tomoaki Suzuki - Department of Radiology, Neurovascular Research Laboratory, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA
İkbal Şencan - Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA
Ge Li - Department of Radiology, Neurovascular Research Laboratory, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA
Paula Reventun - Department of Biology Systems, School of Medicine, University of Alcalá, Madrid, Spain
Emmanuel S Buys - Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA
Hyung-Hwan Kim - Department of Radiology, Neurovascular Research Laboratory, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA
Sava Sakadžić - Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA
Cenk Ayata - Department of Radiology, Neurovascular Research Laboratory, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA
Paul L Huang - Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA
Robert Feil - Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany
Dmitriy N Atochin - Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA
Détails de publication: Journal of cerebral blood flow and metabolism, Vol.39(12), pp.2379-2391
Note de subvention: R01 MH111359 / NIMH NIH HHS K99 MH120053 / NIMH NIH HHS P01 NS055104 / NINDS NIH HHS R01 NS096237 / NINDS NIH HHS R01 NS091230 / NINDS NIH HHS R01 HL125715 / NHLBI NIH HHS R35 CA197743 / NCI NIH HHS R01 CA208205 / NCI NIH HHS P01 CA080124 / NCI NIH HHS
Identifiants: 99154040809311
Unité académique: Institut de Génétique Moléculaire de Montpellier - IGMM
Langue: English
Type de ressource: Journal article