DeltaPKC mediates microcerebrovascular dysfunction in acute ischemia and in chronic hypertensive stress in vivo.
Maintaining cerebrovascular function is a priority for reducing damage following acute ischemic events such as stroke, and under chronic stress in diseases such as hypertension. Ischemic episodes lead to endothelial cell damage, deleterious inflammatory responses, and altered neuronal and astrocyte regulation of vascular function. These, in turn, can lead to impaired cerebral blood flow and compromised blood-brain barrier function, promoting microvascular collapse, edema, hemorrhagic transformation, and worsened neurological recovery. Multiple studies demonstrate that protein kinase C (PKC), a widely expressed serine/threonine kinase, is involved in mediating arterial tone and microvascular function. However, there is no clear understanding about the role of individual PKC isozymes. We show that intraperitoneal injection of deltaV1-1-TAT(47-57) (0.2 mg/kg in 1 mL), an isozyme-specific peptide inhibitor of deltaPKC, improved microvascular pathology, increased the number of patent microvessels by 92% compared to control-treated animals, and increased cerebral blood flow by 26% following acute focal ischemia induced by middle cerebral artery occlusion in normotensive rats. In addition, acute delivery of deltaV1-1-TAT(47-57) in hypertensive Dahl rats increased cerebral blood flow by 12%, and sustained delivery deltaV1-1-TAT(47-57) (5 uL/h, 1 mM), reduced infarct size by 25% following an acute stroke induced by MCA occlusion for 90 min. Together, these findings demonstrate that deltaPKC is an important therapeutic target for protection of microvascular structure and function under both acute and chronic conditions of cerebrovascular stress.
Bright
Rachel
R
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305-5174, USA.
Steinberg
Gary K
GK
Mochly-Rosen
Daria
D
D000818:Animals; D001929:Brain Edema / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D006973:Hypertension / Q000150:complications* / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000473:pathology; D017078:Laser-Doppler Flowmetry / Q000379:methods; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009842:Oligopeptides / Q000627:therapeutic use; D051745:Protein Kinase C-delta / Q000502:physiology*; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley
D009842:Oligopeptides; C477270:Ser-Phe-Asn-Ser-Tyr-Glu-Leu-Gly-Glu-Ser-Leu; D051745:Protein Kinase C-delta