TY - JOUR
T1 - cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice
AU - Shvedova, Maria
AU - Litvak, Maxim M.
AU - Roberts, Jesse D.
AU - Fukumura, Dai
AU - Suzuki, Tomoaki
AU - Şencan, İkbal
AU - Li, Ge
AU - Reventun, Paula
AU - Buys, Emmanuel S.
AU - Kim, Hyung Hwan
AU - Sakadžić, Sava
AU - Ayata, Cenk
AU - Huang, Paul L.
AU - Feil, Robert
AU - Atochin, Dmitriy N.
N1 - Publisher Copyright:
© The Author(s) 2019.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - Cerebral blood flow
KW - cGMP-dependent protein kinase I
KW - ischemia–reperfusion injury
KW - middle cerebral artery occlusion-reperfusion model
KW - stroke
UR - http://www.scopus.com/inward/record.url?scp=85071420697&partnerID=8YFLogxK
U2 - 10.1177/0271678X19870583
DO - 10.1177/0271678X19870583
M3 - Article
C2 - 31423931
AN - SCOPUS:85071420697
SN - 0271-678X
VL - 39
SP - 2379
EP - 2391
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
IS - 12
ER -