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Plasma Kallikrein Contributes to Intracerebral Hemorrhage and Hypertension in Stroke-Prone Spontaneously Hypertensive Rats

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Abstract

Plasma kallikrein (PKa) has been implicated in contributing to hemorrhage following thrombolytic therapy; however, its role in spontaneous intracerebral hemorrhage is currently not available. This report investigates the role of PKa on hemorrhage and hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were fed with a high salt–containing stroke-prone diet to increase blood pressure and induce intracerebral hemorrhage. The roles of PKa on blood pressure, hemorrhage, and survival in SHRSP were examined in rats receiving a PKa inhibitor or plasma prekallikrein antisense oligonucleotide (PK ASO) compared with rats receiving control ASO. Effects on PKa on the proteolytic cleavage of atrial natriuretic peptide (ANP) were analyzed by tandem mass spectrometry. We show that SHRSP on high-salt diet displayed increased levels of PKa activity compared with control rats. Cleaved kininogen was increased in plasma during stroke compared to SHRSP without stroke. Systemic administration of a PKa inhibitor or PK ASO to SHRSP reduced hemorrhage and blood pressure, and improved neurological function and survival compared with SHRSP receiving control ASO. Since PKa inhibition was associated with reduced blood pressure in hypertensive rats, we investigated the effects of PKa on the cleavage of ANP. Incubation of PKa with ANP resulted in the generation fragment ANP5-28, which displayed reduced effects on blood pressure lowering compared with full length ANP. PKa contributes to increased blood pressure in SHRSP, which is associated with hemorrhage and reduced survival. PKa-mediated cleavage of ANP reduces its blood pressure lowering effects and thereby may contribute to hypertension-induced intracerebral hemorrhage.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the National Institute of Health Grant NS107798 (F. S.), NS077006 (E. P. F.), and DK036836 (Joslin’s DRC grant).

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Author notes

  1. Jian Guan and Allen C. Clermont contributed equally to this work.

Authors and Affiliations

  1. Research Division, Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA

    Jian Guan, Loc-Duyen Pham, Tuna Ustunkaya & Fabrício Simão

  2. KalVista Pharmaceuticals, Inc., Cambridge, MA, USA

    Allen C. Clermont & Edward P. Feener

  3. Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA

    Alexey S. Revenko & A. Robert MacLeod

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  1. Jian Guan
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  2. Allen C. Clermont
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Correspondence to Fabrício Simão.

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Ethical Approval

Experiments were performed in accordance with the guidelines of National Institute of Health Guide for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of the Joslin Diabetes Center. This article does not contain any studies with human participants performed by any of the authors.

Conflict of Interest

J. G., L. D. P., T. U., and F. S. declare no competing financial interests. A. S. R. and A. R. M. are employees of Ionis Pharmaceuticals Inc., Carlsbad, CA. A. C. C. and E. P. F. are employees of KalVista Pharmaceuticals Inc., Cambridge, MA.

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Guan, J., Clermont, A.C., Pham, LD. et al. Plasma Kallikrein Contributes to Intracerebral Hemorrhage and Hypertension in Stroke-Prone Spontaneously Hypertensive Rats. Transl. Stroke Res. 13, 287–299 (2022). https://doi.org/10.1007/s12975-021-00929-x

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