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Published on: December 18, 2019
DeltaPKC mediates microcerebrovascular dysfunction in acute ischemia and in chronic hypertensive stress in vivo
Rachel Bright1, Gary K Steinberg, Daria Mochly-Rosen
1Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305-5174, USA.
Insights
Targeting delta protein kinase C (PKC) with deltaV1-1-TAT(47-57) protects brain microvasculature and improves blood flow after stroke. This inhibitor shows promise for treating cerebrovascular stress in both acute and chronic conditions.
Area of Science:
- Neuroscience
- Cardiovascular Biology
- Pharmacology
Background:
- Cerebrovascular function is critical for recovery from stroke and managing hypertension.
- Ischemia and hypertension damage endothelial cells, impairing cerebral blood flow and blood-brain barrier integrity.
- Protein kinase C (PKC) influences vascular tone, but specific isozyme roles in cerebrovascular stress are unclear.
Purpose of the Study:
- To investigate the role of deltaPKC in cerebrovascular dysfunction.
- To evaluate the therapeutic potential of a deltaPKC-specific inhibitor, deltaV1-1-TAT(47-57), in models of acute ischemic stroke and hypertension.
Main Methods:
- Administered deltaV1-1-TAT(47-57) to normotensive and hypertensive rats undergoing middle cerebral artery occlusion (MCAO).
- Assessed microvascular pathology, patent microvessel count, cerebral blood flow, and infarct size.
- Utilized both acute and sustained delivery methods for the inhibitor.
Main Results:
- deltaV1-1-TAT(47-57) increased patent microvessels by 92% and cerebral blood flow by 26% in rats with acute focal ischemia.
- In hypertensive rats, acute deltaV1-1-TAT(47-57) increased cerebral blood flow by 12%.
- Sustained delivery reduced infarct size by 25% in a stroke model.
Conclusions:
- Delta protein kinase C (deltaPKC) plays a significant role in mediating cerebrovascular damage.
- Targeting deltaPKC with deltaV1-1-TAT(47-57) offers a promising therapeutic strategy for protecting microvascular structure and function.
- This approach is effective under both acute ischemic and chronic hypertensive conditions, improving outcomes after stroke.
Abstract:
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.
