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image of The Role of Rho-associated Kinase in the Cognitive Benefits of the ACE Inhibitory Peptide LAP for Hypertension

Abstract

Introduction

This study assessed the effects of the synthesized ACE inhibitory peptide LAP (Leu-Arg-Pro-Val-Ala-Ala) on cognitive impairment in hypertensive rats.

Methods

Rho-associated coiled-coil containing protein kinase (ROCK) activity in peripheral blood mononuclear cells (PBMCs) was initially measured in elderly patients with hypertension and cognitive impairment using western blot analysis. The effect of LAP on the ROCK pathway was studied in a human cell line with ROCK1. Sixteen-week-old male spontaneously hypertensive rats (SHR) received intragastric LAP (500 μg/week) for eight weeks. Cognitive function was assessed using the Morris water maze test, and thoracic aorta remodeling was evaluated by determining the media/lumen ratio through immunohistochemistry. Amyloid beta (Aβ), phosphorylated tau (p-tau), and apoptotic neurons in the hippocampus were examined by western blot analysis and immunohistochemistry. Protein expression and activation related to the ROCK pathway, including moesin, myosin light chain (MLC), and myosin phosphatase target subunit (MYPT), were analyzed in the aorta and hippocampus using western blot and immunohistochemistry.

Results

Hypertensive patients with cognitive impairment showed increased phosphorylated/total myosin-binding subunit ratios in PBMCs, indicating higher ROCK pathway activity. , LAP reduced p-moesin levels, confirming ROCK inhibition. , oral LAP lowered blood pressure and heart rate in SHR models and improved cognitive function. LAP also reduced aortic remodeling, decreased hippocampal Aβ and p-tau deposition, reduced neuronal apoptosis, and increased neuronal survival. Mechanistically, LAP inhibited ROCK pathway activation in the aorta and hippocampus, similar to the ROCK inhibitor fasudil.

Discussion

Hypertension contributes to neurodegenerative changes through the activation of the ROCK signaling pathway. The study found that the ACE inhibitory peptide LAP not only sustainably lowered blood pressure, but also inhibited the ROCK pathway, reducing hippocampal Aβ and p-tau deposition, thereby offering a dual therapeutic approach for hypertension-related cognitive impairment.

Conclusion

LAP alleviated hypertension-related cognitive impairment in SHR by inhibiting the hippocampal ROCK pathway, showing therapeutic potential.

© 2025 Bentham Science Publishers
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2025-09-29
2025-11-02

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References

  1. Santisteban M.M. Iadecola C. Carnevale D. Hypertension, neurovascular dysfunction, and cognitive impairment. Hypertension 2023 80 1 22 34 10.1161/HYPERTENSIONAHA.122.18085
    [Google Scholar]
  2. Wei W. Ma D. Li L. Zhang L. Cognitive impairment in cerebral small vessel disease induced by hypertension. Neural Regen. Res. 2024 19 7 1454 1462 10.4103/1673‑5374.385841 38051887
    [Google Scholar]
  3. Svitlytskyi A.O. Bielenichev I.F. Hancheva O.V. Hrekova T.A. Pathogenetic links between cognitive impairment in arterial hypertension and anatomical and functional characteristics of hippocampal morphology and blood supply (a literature review). Pathologia 2024 21 2 162 169 10.14739/2310‑1237.2024.2.299090
    [Google Scholar]
  4. Qin J. He Z. Wu L. Prevalence of mild cognitive impairment in patients with hypertension: A systematic review and meta-analysis. Hypertens. Res. 2021 44 10 1251 1260 10.1038/s41440‑021‑00704‑3 34285378
    [Google Scholar]
  5. Pei X. Lai S. He X. Mild cognitive impairment in maintenance hemodialysis patients: A cross-sectional survey and cohort study. Clin. Interv. Aging 2018 14 27 32 10.2147/CIA.S178854 30587951
    [Google Scholar]
  6. Huang L. Zhang Y. Wang J. Tang H. Zhou J. Association of anemia and cognitive impairment in patients undergoing maintenance hemodialysis: A cross-sectional study. BMC Nephrol. 2025 26 1 387 10.1186/s12882‑025‑04336‑4 40660151
    [Google Scholar]
  7. Ibrahim S. Bielecki J. Kocabas E. Lifestyle approaches to hypertension for prevention of stroke and vascular cognitive impairment: A realist review protocol. BMJ Open 2024 14 9 088631 10.1136/bmjopen‑2024‑088631 39349379
    [Google Scholar]
  8. Shao Y. Xu Z. Yan Y. The role of Rho/Rho-kinase pathway and the neuroprotective effects of fasudil in chronic cerebral ischemia. Neural Regen. Res. 2015 10 9 1441 1449 10.4103/1673‑5374.165512 26604905
    [Google Scholar]
  9. Li Q. Huang X.J. He W. Neuroprotective potential of fasudil mesylate in brain ischemia-reperfusion injury of rats. Cell. Mol. Neurobiol. 2009 29 2 169 180 10.1007/s10571‑008‑9308‑8 18785000
    [Google Scholar]
  10. Lee E.C. Hong D.Y. Lee D.H. Inflammation and rho-associated protein kinase-induced brain changes in vascular dementia. Biomedicines 2022 10 2 446 10.3390/biomedicines10020446 35203655
    [Google Scholar]
  11. Huang L. Zhao L.B. Yu Z.Y. Long-term inhibition of Rho-kinase restores the LTP impaired in chronic forebrain ischemia rats by regulating GABAA and GABAB receptors. Neuroscience 2014 277 383 391 10.1016/j.neuroscience.2014.07.015 25050822
    [Google Scholar]
  12. te Riet L. van Esch J.H.M. Roks A.J.M. van den Meiracker A.H. Danser A.H.J. Hypertension. Circ. Res. 2015 116 6 960 975 10.1161/CIRCRESAHA.116.303587 25767283
    [Google Scholar]
  13. Hennenberg M. Biecker E. Trebicka J. Defective RhoA/Rho-kinase signaling contributes to vascular hypocontractility and vasodilation in cirrhotic rats. Gastroenterology 2006 130 3 838 854 10.1053/j.gastro.2005.11.029 16530523
    [Google Scholar]
  14. Dee R.A. Mangum K.D. Bai X. Mack C.P. Taylor J.M. Druggable targets in the Rho pathway and their promise for therapeutic control of blood pressure. Pharmacol. Ther. 2019 193 121 134 10.1016/j.pharmthera.2018.09.001 30189292
    [Google Scholar]
  15. Asraf K. Torika N. Apte R.N. Fleisher-Berkovich S. Microglial activation is modulated by captopril: In vitro and in vivo studies. Front. Cell. Neurosci. 2018 12 116 10.3389/fncel.2018.00116 29765306
    [Google Scholar]
  16. Lai A.Y. McLaurin J. Rho‐associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer’s disease. J. Neurochem. 2018 144 5 659 668 10.1111/jnc.14130 28722749
    [Google Scholar]
  17. Gouveia F. Camins A. Ettcheto M. Targeting brain Renin-Angiotensin System for the prevention and treatment of Alzheimer’s disease: Past, present and future. Ageing Res. Rev. 2022 77 101612 10.1016/j.arr.2022.101612 35346852
    [Google Scholar]
  18. Hong F. Junling H. Yi S. The effects of angiotensin-converting enzyme-inhibitory peptide LAP on the left common carotid artery remodeling in spontaneously hypertensive rats. Ir. J. Med. Sci. 2013 182 4 711 718 10.1007/s11845‑013‑0963‑5 23661144
    [Google Scholar]
  19. Hong F. Ming L. Yi S. Zhanxia L. Yongquan W. Chi L. The antihypertensive effect of peptides: A novel alternative to drugs? Peptides 2008 29 6 1062 1071 10.1016/j.peptides.2008.02.005 18384915
    [Google Scholar]
  20. Huang J. Luo M. Fang H. Zheng H. Effects of angiotensin-converting enzyme inhibitory peptide LAP on vascular remodeling. Clin. Exp. Hypertens. 2012 35 6 10.3109/10641963.2012.746353
    [Google Scholar]
  21. Chen K.L. Xu Y. Chu A.Q. Validation of the chinese version of montreal cognitive assessment basic for screening mild cognitive impairment. J. Am. Geriatr. Soc. 2016 64 12 e285 e290 10.1111/jgs.14530 27996103
    [Google Scholar]
  22. Unbekandt M. Croft D.R. Crighton D. A novel small-molecule MRCK inhibitor blocks cancer cell invasion. Cell Commun. Signal. 2014 12 1 54 10.1186/s12964‑014‑0054‑x 25288205
    [Google Scholar]
  23. Kajikawa M. Noma K. Maruhashi T. Rho-associated kinase activity is a predictor of cardiovascular outcomes. Hypertension 2014 63 4 856 864 10.1161/HYPERTENSIONAHA.113.02296
    [Google Scholar]
  24. Hånell A. Marklund N. Structured evaluation of rodent behavioral tests used in drug discovery research. Front. Behav. Neurosci. 2014 8 252 25100962
    [Google Scholar]
  25. Block F. Global ischemia and behavioural deficits. Prog. Neurobiol. 1999 58 3 279 295 10.1016/S0301‑0082(98)00085‑9 10341364
    [Google Scholar]
  26. Van den Broeck L. Sierksma A. Hansquine P. Thonnard D. Callaerts-Vegh Z. D’Hooge R. Comparison between touchscreen operant chambers and water maze to detect early prefrontal dysfunction in mice. Genes Brain Behav. 2021 20 1 12695 10.1111/gbb.12695 32812350
    [Google Scholar]
  27. Cheng H. Men Y. An Y. Overexpression of endothelial S1pr2 promotes blood–brain barrier disruption via JNK/c-Jun/MMP-9 pathway after traumatic brain injury in both in vivo and in vitro models. Front. Pharmacol. 2024 15 1448570 10.3389/fphar.2024.1448570 39679379
    [Google Scholar]
  28. AL-Eitan Laith Naser Alahmad Saif Zuhair Ajeen Sufyan Ali Evaluation of the metabolic activity, angiogenic impacts, and GSK-3β signaling of the synthetic cannabinoid MMB-2201 on human cerebral microvascular endothelial cells. J Cannab Res 2024 6 1 43 10.1186/s42238‑024‑00255‑7
    [Google Scholar]
  29. Ming L. Yi S. Chi L. Long-term antihypertensive effect of angiotensin-converting enzyme inhibitory peptide LAP. Kidney Blood Press. Res. 2011 34 5 358 364 10.1159/000327849 21646816
    [Google Scholar]
  30. Ma J. Li Y. Yang X. Signaling pathways in vascular function and hypertension: Molecular mechanisms and therapeutic interventions. Signal Transduct. Target. Ther. 2023 8 1 168 10.1038/s41392‑023‑01430‑7 37080965
    [Google Scholar]
  31. Mahinrad S. Kurian S. Garner C.R. Cumulative blood pressure exposure during young adulthood and mobility and cognitive function in midlife. Circulation 2020 141 9 712 724 10.1161/CIRCULATIONAHA.119.042502 31747780
    [Google Scholar]
  32. Faraco G. Sugiyama Y. Lane D. Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension. J. Clin. Invest. 2016 126 12 4674 4689 10.1172/JCI86950 27841763
    [Google Scholar]
  33. Kern K.C. Wright C.B. Bergfield K.L. Blood pressure control in aging predicts cerebral atrophy related to small-vessel white matter lesions. Front. Aging Neurosci. 2017 9 132 10.3389/fnagi.2017.00132 28555103
    [Google Scholar]
  34. Khan A.D. Elnagar S. Eltayeb M. The impact of hypertension on cognitive decline and alzheimer’s disease and its management: A systematic review. Cureus 2024 16 7 e65194 10.7759/cureus.65194
    [Google Scholar]
  35. Pacholko A. Iadecola C. Hypertension, neurodegeneration, and cognitive decline. Hypertension 2024 81 5 991 1007 10.1161/HYPERTENSIONAHA.123.21356 38426329
    [Google Scholar]
  36. Yu Y. Wu Y. Wei J. NMDA mediates disruption of blood-brain barrier permeability via Rho/ROCK signaling pathway. Neurochem. Int. 2022 154 105278 10.1016/j.neuint.2022.105278 35017026
    [Google Scholar]
  37. Hwang J.S. Vo T.T.L. Kim M. Involvement of RhoA/ROCK signaling pathway in methamphetamine-induced blood-brain barrier disruption. Biomolecules 2025 15 3 340 10.3390/biom15030340 40149876
    [Google Scholar]
  38. Feng S. Zou L. Wang H. He R. Liu K. Zhu H. RhoA/ROCK-2 pathway inhibition and tight junction protein upregulation by catalpol suppresses lipopolysaccaride-induced disruption of blood-brain barrier permeability. Molecules 2018 23 9 2371 10.3390/molecules23092371 30227623
    [Google Scholar]
  39. Gattu M. Terry A.V. Pauly J.R. Buccafusco J.J. Cognitive impairment in spontaneously hypertensive rats: Role of central nicotinic receptors. Part II. Brain Res. 1997 771 1 104 114 10.1016/S0006‑8993(97)00794‑4 9383013
    [Google Scholar]
  40. McNeil C.J. Myint P.K. Sandu A.L. Increased diastolic blood pressure is associated with MRI biomarkers of dementia-related brain pathology in normative ageing. Age Ageing 2018 47 1 95 100 10.1093/ageing/afx102 29106439
    [Google Scholar]
  41. Sabbatini M. Catalani A. Consoli C. Marletta N. Tomassoni D. Avola R. The hippocampus in spontaneously hypertensive rats: An animal model of vascular dementia? Mech. Ageing Dev. 2002 123 5 547 559 10.1016/S0047‑6374(01)00362‑1 11796140
    [Google Scholar]
  42. Malik R. Georgakis M.K. Neitzel J. Midlife vascular risk factors and risk of incident dementia: Longitudinal cohort and Mendelian randomization analyses in the UK Biobank. Alzheimers Dement. 2021 17 9 1422 1431 10.1002/alz.12320 33749976
    [Google Scholar]
  43. Xu W. Tan L. Wang H.F. Meta-analysis of modifiable risk factors for Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 2015 86 12 jnnp-2015-310548 10.1136/jnnp‑2015‑310548 26294005
    [Google Scholar]
  44. Yau W.Y.W. Shirzadi Z. Yang H.S. Tau mediates synergistic influence of vascular risk and aβ on cognitive decline. Ann. Neurol. 2022 92 5 745 755 10.1002/ana.26460 35880989
    [Google Scholar]
  45. Koch J.C. Tatenhorst L. Roser A.E. Saal K.A. Tönges L. Lingor P. ROCK inhibition in models of neurodegeneration and its potential for clinical translation. Pharmacol. Ther. 2018 189 1 21 10.1016/j.pharmthera.2018.03.008 29621594
    [Google Scholar]
  46. Schmidt S.I. Blaabjerg M. Freude K. Meyer M. RhoA signaling in neurodegenerative diseases. Cells 2022 11 9 1520 10.3390/cells11091520 35563826
    [Google Scholar]
  47. Tawalbeh D. Al-U’datt M.H. Wan Ahmad W.A.N. Ahmad F. Sarbon N.M. Recent advances in in vitro and in vivo studies of antioxidant, ace-inhibitory and anti-inflammatory peptides from legume protein hydrolysates. Molecules 2023 28 6 2423 10.3390/molecules28062423 36985395
    [Google Scholar]
  48. Bartolomei M. Cropotova J. Bollati C. Rainbow trout (Oncorhynchus mykiss) as source of multifunctional peptides with antioxidant, ACE and DPP-IV inhibitory activities. Nutrients 2023 15 4 829 10.3390/nu15040829 36839187
    [Google Scholar]
  49. Wang S. Wang H. Zhang L. Ma T. Tu Z. Identification and in silico screening of novel angiotensin-converting enzyme inhibitory peptides from pacific saury: Interaction mechanism, network pharmacology, stability, Caco-2 monolayer transport. Food Biosci. 2024 61 104576 10.1016/j.fbio.2024.104576
    [Google Scholar]
  50. Wang J. Guo S. Xie X. Characterization of two novel angiotensin converting enzyme-inhibitory peptides from yellow tuna peptides: Inhibitory mechanism, transport route and network pharmacology analysis. Food Res. Int. 2025 209 116232 10.1016/j.foodres.2025.116232 40253180
    [Google Scholar]
  51. Hersh D.S. Wadajkar A.S. Roberts N. Evolving drug delivery strategies to overcome the blood brain barrier. Curr. Pharm. Des. 2016 22 9 1177 1193 10.2174/1381612822666151221150733 26685681
    [Google Scholar]
  52. Yuda N. Tanaka M. Yamauchi K. Effect of the casein-derived peptide met-lys-pro on cognitive function in community-dwelling adults without dementia: A randomized, double-blind, placebo-controlled trial. Clin. Interv. Aging 2020 15 743 754 10.2147/CIA.S253116 32546992
    [Google Scholar]
  53. Min L.J. Kobayashi Y. Mogi M. Administration of bovine casein-derived peptide prevents cognitive decline in Alzheimer disease model mice. PLoS One 2017 12 2 0171515 10.1371/journal.pone.0171515 28158298
    [Google Scholar]
  54. Gregory K.S. Cozier G.E. Schwager S.L.U. Sturrock E.D. Acharya K.R. Structural insights into the inhibitory mechanism of angiotensin‐I‐converting enzyme by the lactotripeptides IPP and VPP. FEBS Lett. 2024 598 2 242 251 10.1002/1873‑3468.14768 37904282
    [Google Scholar]
  55. Zhong G. Long H. Zhou T. Blood-brain barrier Permeable nanoparticles for Alzheimer’s disease treatment by selective mitophagy of microglia. Biomaterials 2022 288 121690 10.1016/j.biomaterials.2022.121690 35965114
    [Google Scholar]
  56. Wang C. Wang S. Xue Y. Intravenous administration of blood–brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system. Nat. Biotechnol. 2024 10.1038/s41587‑024‑02487‑7 39587229
    [Google Scholar]
  57. Mi X. Cao Y. Li Y. The non-peptide angiotensin-(1–7) mimic AVE 0991 attenuates delayed neurocognitive recovery after laparotomy by reducing neuroinflammation and restoring blood-brain barrier integrity in aged rats. Front. Aging Neurosci. 2021 13 624387 10.3389/fnagi.2021.624387 33658918
    [Google Scholar]
  58. Kangussu L.M. Almeida-Santos A.F. Fernandes L.F. Transgenic rat with overproduction of ubiquitous angiotensin-(1-7) presents neuroprotection in a model of ischemia and reperfusion. Brain Res. Bull. 2023 192 184 191 10.1016/j.brainresbull.2022.11.017 36435363
    [Google Scholar]
  59. Hong J. Li Y. Chen L. A53T α-synuclein mutation increases susceptibility to postoperative delayed neurocognitive recovery via hippocampal Ang-(1–7)/MasR axis. Biochem. Pharmacol. 2024 224 116261 10.1016/j.bcp.2024.116261 38705534
    [Google Scholar]
  60. Li Z. He H. Liu J. Preparation and Vasodilation Mechanism of Angiotensin-I-Converting Enzyme Inhibitory Peptide from Ulva prolifera Protein. Mar. Drugs 2024 22 9 398 10.3390/md22090398 39330279
    [Google Scholar]
  61. Wu N. Wuhanqimuge, Shuang Q. Screening, characterization, and mechanistic evaluation of angiotensin converting enzyme inhibitory peptides derived from milk fermented with lactobacillus delbrueckii QS306 with and without ultrahigh-pressure treatment. J. Agricult. Food Chem. 2023 71 45 17420 17431 10.1021/acs.jafc.3c03752
    [Google Scholar]
  62. Ma T. Liu L. Wang P. Xue Y. Evidence for involvement of ROCK signaling in bradykinin-induced increase in murine blood–tumor barrier permeability. J. Neurooncol. 2012 106 2 291 301 10.1007/s11060‑011‑0685‑3 21892742
    [Google Scholar]
  63. Lu Y. Wang Y. Huang D. Inhibitory mechanism of angiotensin-converting enzyme inhibitory peptides from black tea. J. Zhejiang Univ. Sci. B 2021 22 7 575 589 10.1631/jzus.B2000520 34269010
    [Google Scholar]
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The Role of Rho-associated Kinase in the Cognitive Benefits of the ACE Inhibitory Peptide LAP for Hypertension
Bentham Science Publishers ; https://doi.org/10.2174/0115665240408227250917073210
/content/journals/cmm/10.2174/0115665240408227250917073210
/content/journals/cmm/10.2174/0115665240408227250917073210
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  • Article Type:     Research Article
Keywords: LAP (Leu-Arg-Pro-Val-Ala-Ala) ; hypertension ; ACE inhibitory peptide ; Rho-associated kinase ; vascular remodeling ; cognitive impairment

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