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

Authors :
Kato, Taisuke
Manabe, Ri-Ichiroh
Igarashi, Hironaka
Kametani, Fuyuki
Hirokawa, Sachiko
Sekine, Yumi
Fujita, Natsumi
Saito, Satoshi
Kawashima, Yusuke
Hatano, Yuya
Ando, Shoichiro
Nozaki, Hiroaki
Sugai, Akihiro
Uemura, Masahiro
Fukunaga, Masaki
Sato, Toshiya
Koyama, Akihide
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
Source :
Journal of Clinical Investigation. November 15, 2021, Vol. 131 Issue 22
Publication Year :
2021

Abstract

Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor [beta] (TGF-[beta]) signaling. Here, we show that [HTRA1.sup.-/-] mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-[beta] binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.<br />Introduction Cerebral small vessel disease (CSVD) is a sporadic and hereditary arteriopathy of the cerebral small vessels that results in dementia and gait disturbance (1). The molecular mechanism of CSVD [...]

Details

Language :
English
ISSN :
00219738
Volume :
131
Issue :
22
Database :
Gale General OneFile
Journal :
Journal of Clinical Investigation
Publication Type :
Academic Journal
Accession number :
edsgcl.685496851
Full Text :
https://doi.org/10.1172/JCI140555