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01-04-2022 | Stroke | Original Article

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

Authors: Jian Guan, Allen C. Clermont, Loc-Duyen Pham, Tuna Ustunkaya, Alexey S. Revenko, A. Robert MacLeod, Edward P. Feener, Fabrício Simão

Published in: Translational Stroke Research | Issue 2/2022

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 ANP_5-28, 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.

Brott T, Thalinger K, Hertzberg V. Hypertension as a risk factor for spontaneous intracerebral hemorrhage. Stroke. 1986;17:1078–83.PubMedCrossRef

Kazui SMK, Sawada T, Yamaguchi T. Predisposing factors to enlargement of spontaneous intracerebral hemorrhage. Stroke. 1997;28:2370–5.PubMedCrossRef

Qureshi AI, Mendelow AD, Hanley DF. Prevalence of elevated blood pressure in 563,704 adult patients with stroke presenting to the ED in the United States. Am J Emerg Med. 2007;25:32–8.PubMedPubMedCentralCrossRef

Carlberg B, Asplund K, Hagg E. Factors influencing admission blood pressure levels in patients with acute stroke. Stroke. 1991;22:527–30.PubMedCrossRef

Sato S, Carcel C, Anderson CS. Blood pressure management after intracerebral hemorrhage. Curr Treat Options Neurol. 2015;17:49.PubMedCrossRef

Willmot N, Leonardi-Bee J, Bath PMW. High blood pressure in acute stroke and subsequent outcome: a systematic review. Hypertension. 2004;43:18–24.PubMedCrossRef

Lawes CMM, Bennett DA, Feigin VL, Rodgers A. Blood pressure and stroke. Stroke. 2004;35:776–85.PubMedCrossRef

Schmaier AH, McCrae KR. The plasma kallikrein-kinin system: its evolution from contact activation. J Thromb Haemost. 2007;5:2323–9.PubMedCrossRef

Liu J, Gao BB, Clermont AC, Blair P, Chilcote TJ, Sinha S, et al. Hyperglycemia-induced cerebral hematoma expansion is mediated by plasma kallikrein. Nat med. 2011;17:206–10.PubMedPubMedCentralCrossRef

10.

Simao F, Feener EP. The effects of the contact activation system on hemorrhage. Front Med. 2017;4:121.CrossRef

11.

Liu J, Clermont AC, Gao BB, Feener EP. Intraocular hemorrhage causes retinal vascular dysfunction via plasma kallikrein. Invest Ophthalmol Vis Sci. 2013;54:1086–94.PubMedPubMedCentralCrossRef

12.

Simao F, Ustunkaya T, Clermont AC, Feener EP. Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke. Blood. 2017;129:2280–90.PubMedPubMedCentralCrossRef

13.

Revenko AS, Gao D, Crosby JR, Bhattachariee G, Zhao C, May C, et al. Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. Blood. 2011;118:5302–11.PubMedPubMedCentralCrossRef

14.

Phipps JA, Clermont AC, Sinha S, Chilcote TJ, Bursell SE, Feener EP. Plasma kallikrein mediates angiotensin II type 1 receptor-stimulated retinal vascular permeability. Hypertension. 2009;53:175–81.PubMedCrossRef

15.

Jaffa AA, Durazo-Arvizu R, Zheng D, Lackland DT, Srikanth S, Garvey WT, et al. Plasma prekallikrein: a risk marker for hypertension and nephropathy in type 1 diabetes. Diabetes. 2003;52:1215–21.PubMedCrossRef

16.

Ferrone JD, Bhattacharjee G, Revenko AS, Zanardi TA, Warren MS, Derosier FJ, et al. IONIS-PKKKRx a novel antisense inhibitor of prekallikrein and bradykinin production. Nucleic Acid Ther. 2019;29:82–91.PubMedPubMedCentralCrossRef

17.

Zhang F, Guo RM, Yang M, Wen XH, Shen J. A stable focal cerebral ischemia injury model in adult mice: assessment using 7T MR imaging. AJNR Am J Neuroradiol. 2012;33:935–9.PubMedPubMedCentralCrossRef

18.

Gao BB, Chen X, Timothy N, Aiello LP, Feener EP. Characterization of the vitreous proteome in diabetes without diabetic retinopathy and diabetes with proliferative diabetic retinopathy. J Proteome Res. 2008;7:2516–25.PubMedCrossRef

19.

Mori N, Nakao K, Kihara M, Sugawara A, Sakamoto M, Yamori Y, et al. Decreased content in left atrium and increased plasma concentration of atrial natriuretic polypeptide in spontaneously hypertensive rats (SHR) and SHR stroke-prone. Biochem Biophys Res Commun. 1986;135:74–81.CrossRef

20.

De Bold AJ. Atrial natriuretic factor: a hormone produced by heart. Science. 1985;230:767–70.PubMedCrossRef

21.

Oparil S. The elusive role of atrial natriuretic peptide in hypertension. Mayo Clin Proc. 1995;70:1015–7.PubMedCrossRef

22.

Romero M, Caniffi C, Bouchet G, Costa MA, Elesgaray R, Arranz C, et al. Chronic treatment with atrial natriuretic peptide in spontaneously hypertensive rats: beneficial renal effects and sex differences. PLoS One. 2015;10:e0120362.

23.

Thibault G, Garcia R, Cantin M, Genest J. Atrial natriuretic factor and urinary kallikrein in the rat: antagonistic factors? Can J Physiol Pharmacol. 1984;62:645–9.PubMedCrossRef

24.

Briggs J, Marin-Grez M, Steipe B, Schubert G, Schnermann J. Inactivation of atrial natriuretic substance by kallikrein. Arm J Physiol. 1984;247:F480-484.

25.

Li B, Tom JY, Oare D, Yen R, Fairbrother WJ, Wells JA, et al. Minimization of a polypeptide hormone. Science. 1995;270:1657–9.PubMedCrossRef

26.

Zeng J, Zhang Y, Mo J, Su Z, Huang R. Two-kidney, two clip renovascular hypertensive rats can be used as stroke-prone rats. Stroke. 1998;29:1709–14.CrossRef

27.

Arribas SM, Costa R, Salomone S, Morel N, Godfraind T, McGrath JC. Functional reduction and associated cellular rearrangement in SHRSP rat basilar arteries are affected by salt load and calcium antagonist treatment. J Cereb Blood Flow Metab. 1999;19:517–27.PubMedCrossRef

28.

Arribas SM, Gordon JF, Daly CJ, Dominiczak AF, McGrath JC. Confocal microscopic characterization of a lesion in a cerebral vessel of the stroke-prone spontaneously hypertensive rat. Stroke. 1996;27:1118–23.PubMedCrossRef

29.

Lee JM, Zhai G, Liu Q, Gonzales ER, Yin K, Yan P, et al. Vascular permeability precedes spontaneous intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats. Stroke. 2007;38:3289–91.PubMedCrossRef

30.

Smeda JS, Daneshtalab N. The effects of poststroke captopril and losartan treatment on cerebral blood flow autoregulation in SHRSP with hemorrhagic stroke. J Cereb Blood Flow Metab. 2011;31:476–85.PubMedCrossRef

31.

Smeda JS. Hemorrhagic stroke development in spontaneously hypertensive rats fed a North American. Japanese-style diet Stroke. 1989;20:1212–8.PubMed

32.

Del Bigio MR, Yan HJ, Kozlowski P, Sutherland GR, Peeling J. Serial magnetic resonance imaging of rat brain after induction of renal hypertension. Stroke. 1999;30:2440–7.PubMedCrossRef

33.

Okamoto K, Ohta Y, Chikugo T, Shiokawa H, Morita N. Chronic treatment with captopril, SQ 29,852, hydralazine and a 33% fish meal diet in malignant stroke-prone spontaneously hypertensive rats. J Hypertens. 1991;9:1105–7.PubMed

34.

Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665.

35.

Horning B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation. 1997;95:1115–8.CrossRef

36.

Campbell DJ, Krum H, Esler MD. Losartan increases bradykinin levels in hypertensive humans. Circulation. 2005;111:315–20.PubMedCrossRef

37.

Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, White A, Cushman WC, White W, Sica D, Ferdinand K, Giles TD, Falkner B, Carey RM. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008;117:e510–26.PubMedCrossRef

38.

Mohr JP, Marti-Vilalta JL. Lacunes. In: Barnett HJM, Mohr JP, Stein BM, Yatsu FM, editors. Stroke: pathophysiology, diagnosis, and management. 3rd ed. New York, NY: Churchill Livingstone; 1998. p. 599–622.

39.

Schreiber S, Bueche CZ, Garz C, Braun H. Blood brain barrier breakdown as the starting point of cerebral small vessel disease? – New insights from a rat model. Exp Transl Stroke Med. 2013;5:4.PubMedPubMedCentralCrossRef

40.

Gob E, Reymann S, Langhauser F, Schuhmann MK, Kraft P, Thielmann I, et al. Blocking of plasma kallikrein ameliorates stroke by reducing thromboinflammation. Ann Neurol. 2015;77:784–803.PubMedCrossRef

41.

Liu J, Gao BB, Feener EP. Proteomic identification of novel plasma kallikrein substrates in the astrocyte secretome. Transl Stroke Res. 2010;1:276–86.PubMedCrossRef

42.

Bailey EL, Wardlaw JM, Graham D, Dominiczak AF, Sudlow CL, Smith C. Cerebral small vessel endothelial structural changes predate hypertension in stroke-prone spontaneously hypertensive rats: a blinded, controlled immunohistochemical study of 5- to 21-week-old rats. Neuropathol Appl Neurobiol. 2011;37:711–26.PubMedCrossRef

43.

Lee JM, Zhai G, Liu Q, et al. Vascular permeability precedes spontaneous intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats. Stroke. 2007;38:3289–91.PubMedCrossRef

44.

Quick S, Moss J, Rajani RM, Williams A. A vessel for change: endothelial dysfunction in cerebral small vessel disease. Trends Neusoci. 2021;44:289–305.CrossRef

45.

Rajani RM, Quick S, Ruigrok SR, Graham D, Harris SE, Verhaaren BFJ, Fornage M, Seshadri S, Atanur SS, Dominiczak AF, Smith C, Wardlaw JM, Williams A. Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats. Sci Transl Med. 2018;10:eaam9507.

46.

Tagami M, Kubota A, Sunaga T, et al. Increased transendothelial channel transport of cerebral capillary endothelium in stroke-prone SHR. Stroke. 1993;14:591–6.CrossRef

47.

Fredriksson K, Kalimo H, Westergren I, et al. Blood-brain barrier leakage and brain edema in stroke-prone spontaneously hypertensive rats: effect of chronic sympathectomy and low protein/high salt diet. Acta Neuropathol (Berl). 1987;74:259–68.CrossRef

48.

Tomimoto H, Akiguchi I, Sunaga T, et al. Alterations of the blood-brain barrier and glial cells in white-matter lesions in cerebrovascular and Alzheimer’s disease patients. Stroke. 1996;27:2096–2074.CrossRef

49.

Da Fonseca AC, Matias D, Garcia C, Amaral R, Geraldo LH, Freitas C, Lima FR. The impact of microglia activation on blood-brain barrier in brain diseases. Front Cell Neurosci. 2014;8:362.PubMedPubMedCentralCrossRef

50.

Takeuchi S, Nagatani K, Otani N, Nawashiro H, Sugawara T, Wada K, Mori K. Hydrogen improves neurological function through attenuation of blood-brain barrier disruption in spontaneously hypertensive stroke-prone rats. BMC Neurosci. 2015;16:22.PubMedPubMedCentralCrossRef

51.

Yamamoto E, Tamamaki N, Nakamura T, Kataoka K, Tokutomi Y, Dong YF, Fukuda M, Matsuba S, Ogawa H, Kim-Mitsuyama S. Excess salt causes cerebral neuronal apoptosis and inflammation in stroke-prone hypertensive rats through angiotensin II-induced NADPH oxidase activation. Stroke. 2008;39:3049–56.PubMedCrossRef

52.

Marks L, Carswell HV, Peters EE, Graham DI, Patterson J, Dominiczak AF, Macrae IM. Characterization of the microglial response to cerebral ischemia in the stroke-prone spontaneously hypertensive rat. Hypertension. 2001;38:116–22.PubMedCrossRef

53.

Kato J, Kida O, Nakamura S, Sasaki A, Kodoma K, Tanaka K. Atrial natriuretic polypeptide (ANP) in the development of spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP). Biochem Biophys Res Commun. 1987;143:316–22.PubMedCrossRef

54.

John SWM, Krege JH, Oliver PM, Hagaman JR, Hodgin JB, Pang SC, et al. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science. 1995;267:679–81.PubMedCrossRef

55.

Steinhelper ME, Cochrane KL, Field LJ. Hypotension in transgenic mice expressing atrial natriuretic factor fusion genes. Hypertension. 1990;16:301–7.PubMedCrossRef

56.

Klinger JR, Petit RD, Curtin LA, Warburton RR, Wrenn DS, Steinhelper ME, et al. Cardiopulmonary responses to chronic hypoxia in transgenic mice that overexpress ANP. J Appl Physiol. 1993;75:198–205.PubMedCrossRef

57.

Janssen WNT, de Zeuw D, van der Hem GK, de Jong PE. Antihypertensive effect of a 5-day infusion of atrial natriuretic factor in humans. Hypertension. 1989;13:640–6.PubMedCrossRef

Title: Plasma Kallikrein Contributes to Intracerebral Hemorrhage and Hypertension in Stroke-Prone Spontaneously Hypertensive Rats
Authors: Jian Guan
Allen C. Clermont
Loc-Duyen Pham
Tuna Ustunkaya
Alexey S. Revenko
A. Robert MacLeod
Edward P. Feener
Fabrício Simão
Publication date: 01-04-2022
Publisher: Springer US
Keywords: Stroke
Hypertension
Hypertension
Published in: Translational Stroke Research / Issue 2/2022
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI: https://doi.org/10.1007/s12975-021-00929-x

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

Abstract

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Springer Medicine

Abstract

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