Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model

Kato, Taisuke; Manabe, Ri-ichiroh; Igarashi, Hironaka; Kametani, Fuyuki; Hirokawa, Sachiko; Sekine, Yumi; Fujita, Natsumi; Saitô, Satoshi; Kawashima, Yusuke; Hatano, Yuya; Ando, Shoichiro; Nozaki, Hiroaki; Sugai, Akihiro; Uemura, Masahiro; Fukunaga, Masaki; Sato, Toshiya; Koyama, Akira; Saito, Rie; Sugie, Atsushi; Toyoshima, Yasuko; Kawata, Hirotoshi; Murayama, Shigeo; Matsumoto, Masaki; Kakita, Akiyoshi; Hasegawa, Masato; Ihara, Masafumi; Kanazawa, Masato; Nishizawa, Masatoyo; Tsuji, Shoji; Onodera, Osamu

doi:10.1172/jci140555

Cited by 19 publications

(21 citation statements)

References 100 publications

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“…Thus, only C3 and C1QC were consistently quantified but showed no significant changes in HTRA1 −/− mice. Importantly, this finding was fully confirmed in a recent independent study on HTRA1-deficient mice [ 34 ]. Also, seven of the eight proteins (OLFML3, APOE, VTN, TIMP3, SERPINE2, CLU and NDP) have previously been shown in proteolysis assays to be HTRA1 substrates [ 1 , 9 , 14 , 44 , 64 , 72 ] (Fig.…”

Section: Resultssupporting

confidence: 69%

“…Similar proteomic changes in HTRA1 deficient mice were recently reported by Kato et. al [ 34 ]. For most proteins in vitro cleavage data have been reported earlier.…”

Section: Resultsmentioning

confidence: 99%

“…We hypothesize that, under physiological conditions, HTRA1 degrades excess proteins thus safeguarding extracellular proteostasis. Support for this comes from studies demonstrating HTRA1-mediated degradation of oligomeric/fibrillar Aβ and tau species [ 19 , 49 , 56 ] and from previous findings showing an accumulation of multiple constituents of the vascular ECM in Htra1-deficient mice [ 34 , 72 ]. In CAA type 1 and CADASIL, HTRA1 is recruited into the vascular Aβ and Notch3 ECD deposits characterizing these vasculopathies.…”

Section: Discussionmentioning

confidence: 96%

“…The majority of highly enriched proteins shared by our CAA type 1 and CADASIL profiles also accumulate in brain microvessels of Htra1 knockout mice [ 34 , 72 ] and thus represent putative HTRA1 substrates. Accordingly, HTRA1-mediated processing of a number of these proteins has been demonstrated by us and others in in-vitro cleavage assays [ 1 , 9 , 14 , 44 , 64 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

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Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates

Zellner

Müller

Lindner

et al. 2022

acta neuropathol commun

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Cerebral amyloid angiopathy (CAA) is an age-related condition and a major cause of intracerebral hemorrhage and cognitive decline that shows close links with Alzheimer's disease (AD). CAA is characterized by the aggregation of amyloid-β (Aβ) peptides and formation of Aβ deposits in the brain vasculature resulting in a disruption of the angioarchitecture. Capillaries are a critical site of Aβ pathology in CAA type 1 and become dysfunctional during disease progression. Here, applying an advanced protocol for the isolation of parenchymal microvessels from post-mortem brain tissue combined with liquid chromatography tandem mass spectrometry (LC–MS/MS), we determined the proteomes of CAA type 1 cases (n = 12) including a patient with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), and of AD cases without microvascular amyloid pathology (n = 13) in comparison to neurologically healthy controls (n = 12). ELISA measurements revealed microvascular Aβ1-40 levels to be exclusively enriched in CAA samples (mean: > 3000-fold compared to controls). The proteomic profile of CAA type 1 was characterized by massive enrichment of multiple predominantly secreted proteins and showed significant overlap with the recently reported brain microvascular proteome of patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease (SVD) characterized by the aggregation of the Notch3 extracellular domain. We found this overlap to be largely attributable to the accumulation of high-temperature requirement protein A1 (HTRA1), a serine protease with an established role in the brain vasculature, and several of its substrates. Notably, this signature was not present in AD cases. We further show that HTRA1 co-localizes with Aβ deposits in brain capillaries from CAA type 1 patients indicating a pathologic recruitment process. Together, these findings suggest a central role of HTRA1-dependent protein homeostasis in the CAA microvasculature and a molecular connection between multiple types of brain microvascular disease.

show abstract

Section: Resultssupporting

confidence: 69%

“…Similar proteomic changes in HTRA1 deficient mice were recently reported by Kato et. al [ 34 ]. For most proteins in vitro cleavage data have been reported earlier.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates

Zellner

Müller

Lindner

et al. 2022

acta neuropathol commun

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show abstract

“…Kato et al found the mRNA expression of Adamtsl2 that is involved in forming the extracellular matrix network was suppressed by candesartan treatment, therefore, normalizing the vascular distensibility and cerebral blood flow in arteriopathy. 25 The increasing expressions of Adamtsl2 in heart disease were also observed. 26 , 27 SPON2 belongs to the F-spondin family of secreted extracellular matrix proteins, and act as pattern recognition receptors to regulate immunity.…”

Section: Discussionmentioning

confidence: 88%

The Transcriptional Landscapes and Key Genes in Brain Arteriovenous Malformation Progression in a Venous Hypertension Rat Model Revealed by RNA Sequencing

Li¹,

Tao²,

Huang³

et al. 2022

JIR

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Background Brain arteriovenous malformations (bAVM) are abnormal vascular lesions characterized by direct connections between arteries and veins without an intervening capillary bed. The primary goal for brain AVM treatment is to prevent rupture and hemorrhage; however, the underlying molecular mechanisms are still unknown. Methods We constructed venous hypertension (VH) rat model with end-to-end anastomosis of the proximal left common carotid artery and the left distal external jugular vein. Thirty-eight adult rats were randomly assigned to four groups: the 0-week (n=5), the 1-week VH group (n=12), the 3-week VH group (n=9), and the 6-week VH group (n=12). We measured the hemodynamics and diameter of the arterialized veins. An RNA sequencing of arterialized veins was conducted, followed by comprehensive bioinformatics analysis to identify key genes and biological pathways involved in VH progression. The candidate genes from RNA-Seq were validated by RT-qPCR and immunostaining in human tissues. Results We observed high-flow and low resistance characteristics in VH models. A total of 317 upregulated and 258 downregulated common genes were consistently differentially expressed during VH progression. Thirteen co-expression modules were obtained by WGCNA analysis, and 4 key modules were identified. Thirteen genes: Adamts8, Adamtsl3, Spon2, Adamtsl2, Chad, Itga7, Comp, Itga8, Bmp6, Fst, Smad6, Smad7, Grem1, and Nog with differential expressions were identified using the density of maximum neighborhood component (DMNC) algorithm in Cytohubba. The expression of five potential genes (Adamts8, Adamtsl3, Spon2, Adamtsl2, Itga8) were increased in RT-qPCR, while in human bAVM tissue, the protein levels of Adamtsl2 and Itga8 were significant elevated and Spon2 and Adamtsl3 were decreased. Conclusion The identified gene networks of Adamtsl3, Spon2, Adamtsl2, and Itga8 provided key genes for further intervention.

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Neuroprotective effects of oral metformin before stroke on cerebral small-vessel disease

Akiyama,

Yamashiro,

Ninomiya

et al. 2024

Journal of the Neurological Sciences

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Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model

Cited by 19 publications

References 100 publications

Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates

Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates

The Transcriptional Landscapes and Key Genes in Brain Arteriovenous Malformation Progression in a Venous Hypertension Rat Model Revealed by RNA Sequencing

Neuroprotective effects of oral metformin before stroke on cerebral small-vessel disease

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