APBN New Site

APBN Developing Site

Repurposing Antihypertensive Drugs for Hereditary Cerebral Small Vessel Disease

Candesartan, which suppresses the accumulation of extracellular matrix proteins in the vessel wall of a mouse model, shows promise for treating age-related cerebral arteriopathy.

Cerebral small vessel disease (CSVD) is an umbrella term describing various abnormalities related to arterioles, capillaries, venules, and small arteries in the brain. Due to ageing and high blood pressure among other factors, these blood vessels can be damaged and consequently lead to abnormal gait, dementia, psychiatric disorders, and stroke. Currently, no specific preventive or therapeutic strategy is available to improve this condition. However, considering our rapidly ageing society and the high prevalence of CSVD amongst the elderly, an effective method of treatment is urgently needed.

Fortunately, in their novel study of the molecular pathogenesis of cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), the hereditary form of CSVD, Niigata University and RIKEN scientists have found that the antihypertensive drug candesartan cilexetil may offer a promising avenue for treatment.

Initially reported as a recessive hereditary disease but now known to show dominant traits, CARASIL develops as a result of mutations of the HTRA1 (High Temperature Requirement A Serine Peptidase 1) gene. In recent years, HTRA1 has been attracting attention as a risk gene for age-related CSVD as 1 in 450 people in the UK reportedly carries the risk mutation. Because the changes observed in CARASIL arteriopathy, such as the thickening of the intima, resemble age-related CSVD, the researchers believed that studying the pathogenesis of CARASIL could illuminate a path for future research in age-related CSVD.

To precisely determine the molecular mechanisms behind the development of CARASIL, the team engineered aged HTRA1 gene-knockout mice. In the mice, they detected the accumulation of proteins in their cerebral arteries. When the composition of these accumulated proteins was analysed, it was found that about 40 per cent of the proteins were matrisomes, which include extracellular matrix and extracellular matrix-binding proteins. Most importantly, fibronectin, a central component of the matrisome and a known substrate of HTRA1, was also present.

Through further investigation, the accumulation of matrisome proteins was found to increase substantially with age. This is also observed in patients with CARASIL, albeit the accumulation being detected in the inner membrane. Furthermore, cerebral blood flow decreased and cerebral blood vessels appeared to grow stiffer in the HTRA1-deficient mice.

“This change in CARASIL may be related to the inadequate degradation of matrisomes due to HTRA1 dysfunction and the increase in matrisomes due to ageing,” said Prof. Osamu Onodera, director of the Niigata University Brain Research Institute.

When the team tested the therapeutic effects of the antihypertensive drug candesartan cilexetil, they found that candesartan successfully inhibited the accumulation of fibronectin in other organs. They also observed that candesartan treatment effectively reduced matrisomal protein accumulation and normalised vascular stiffness and cerebral flow.

“What we saw was remarkable. Even when HTRA1 was completely absent, 61 per cent of the accumulated matrisomal proteins were suppressed. This effect is not accompanied by an increase in degrading enzymes or suppression of matrisome protein expression. We think it is important to clarify this mechanism in the future,” revealed Dr. Taisuke Kato, an associate professor in the research team.

With these results, the team has shed light on the importance and possibility of targeting matrisome protein accumulation using candesartan to ameliorate arteriopathy. While further research needs to be conducted to confirm the drug’s effectiveness even after arteriopathy has progressed, their findings are expected to broaden options for preventing CSVD progression.

“Matrisomes also accumulate in other hereditary and in age-related CSVDs. A protective strategy for cerebral blood vessels to prevent matrisome accumulation with inexpensive oral drugs could be a major change for age-related brain diseases,” said Prof. Onodera. [APBN]

Source: Kato et al. (2021). Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model. Journal of Clinical Investigation, 131(22), e140555.