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

Maria Shvedova, Maxim M. Litvak, Jesse D. Roberts, 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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2379-2391
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume39
Issue number12
DOIs
Publication statusPublished - 1 Dec 2019
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice'. Together they form a unique fingerprint.

  • Cite this

    Shvedova, M., Litvak, M. M., Roberts, J. D., Fukumura, D., Suzuki, T., Şencan, İ., Li, G., Reventun, P., Buys, E. S., Kim, H. H., Sakadžić, S., Ayata, C., Huang, P. L., Feil, R., & Atochin, D. N. (2019). cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice. Journal of Cerebral Blood Flow and Metabolism, 39(12), 2379-2391. https://doi.org/10.1177/0271678X19870583