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J Cereb Blood Flow Metab. 2019 Dec;39(12):2379-2391. doi: 10.1177/0271678X19870583. Epub 2019 Aug 18.

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

Author information

1
Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
2
Tomsk Polytechnic University, RASA Center, Tomsk, Russian Federation.
3
Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
4
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital, Boston, MA, USA.
5
Department of Radiology, Neurovascular Research Laboratory, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
6
Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
7
Department of Biology Systems, School of Medicine, University of Alcalá, Madrid, Spain.
8
Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.

Abstract

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 mm3; females: 93 ± 12 mm3, 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.

KEYWORDS:

Cerebral blood flow; cGMP-dependent protein kinase I; ischemia–reperfusion injury; middle cerebral artery occlusion-reperfusion model; stroke

PMID:
31423931
PMCID:
PMC6893979
[Available on 2020-12-01]
DOI:
10.1177/0271678X19870583

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