Fasudil (HA-1077) is a selective RhoA/
Rho kinase (ROCK) inhibitor.[9] ROCK is an enzyme that plays an important role in mediating vasoconstriction and vascular remodeling in the pathogenesis of pulmonary hypertension. ROCK induces vasoconstriction by phosphorylating the myosin-binding subunit of myosin light chain (MLC) phosphatase, thus decreasing MLC phosphatase activity and enhancing vascular smooth muscle contraction.[9]
ACE expression
Angiotensin-converting enzyme (ACE) is an enzyme that catalyzes the conversion of
angiotensin-I (Ang-I) to
angiotensin-II (Ang-II). Ang-II is a peptide hormone which increases blood pressure by initiating
vasoconstriction and
aldosterone secretion. ROCK increases ACE expression and activity in pulmonary hypertension. By inhibiting ROCK with fasudil, circulating ACE and Ang-II are reduced, leading to a decrease in pulmonary vascular pressure.[10]
eNOS expression
Endothelial nitric oxide synthase (eNOS) mediates the production of the vasodilator
nitric oxide (NO). Pulmonary arterial cell cultures treated with fasudil showed a significant increase in eNOS mRNA levels in a dose dependent manner, and the half-life of eNOS mRNA increased 2-folds. These findings suggested that ROCK inhibition with fasudil increases eNOS expression by stabilizing eNOS mRNA, which contributed to an increase of NO level to enhance vasodilation.[11]
ERK activation
The proliferative effects of ROCK on vascular endothelial cells is due to the activation of
extracellular signal-regulated kinase (ERK).[12] ERK mediates cell proliferation via the phosphorylation of p27Kip1, thus accelerating the degradation rate of
p27Kip1.[13] p27Kip1 is a cyclin-dependent kinase (CDK) inhibitor which down-regulates cell cycle by binding cyclin-CDK complex.[14] Human pulmonary arterial smooth muscle cells treated with fasudil showed a decrease in cell proliferation in a dose-dependent manner. Fasudil also decreases ERK activities, as well as increases level of p27Kip1. This suggested that the anti-proliferative effects of fasudil is due to the decrease of ERK activities via the inhibition of ROCK.[12]
Direct inhibition of α-synuclein aggregation
In addition to ROCK inhibition, fasudil has also been demonstrated to directly modulate the aggregation of
α-synuclein, both in vitro and in cellular models of neurodegenerative disease.[15] Aggregation of α-synuclein is a major hallmark of
Parkinson's disease, and has also been observed in other neurodegenerative diseases. Physical interactions between α-synuclein and fasudil have been shown to take place with α-synuclein in the
intrinsically disordered state, which places fasudil among a small number of drug-like molecules that directly interact with intrinsically disordered proteins.[16]
See also
Ripasudil, a fasudil derivative used to treat glaucoma and ocular hypertension
^Shibuya M, Suzuki Y (Sep 1993). "[Treatment of cerebral vasospasm by a protein kinase inhibitor AT 877]". Nō to Shinkei - Brain and Nerve (in Japanese). 45 (9): 819–24.
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^Kumar M, Bansal N (October 2018). "Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer's disease: Involvement of PI3-kinase, eNOS and NFκB". Behavioural Brain Research. 351: 4–16.
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^Song X, He R, Han W, Li T, Xie L, Cheng L, et al. (April 2019). "Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats". Journal of Neuroscience Research. 97 (4): 506–519.
doi:
10.1002/jnr.24355.
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abLiu AJ, Ling F, Wang D, Wang Q, Lü XD, Liu YL (Oct 2011). "Fasudil inhibits platelet-derived growth factor-induced human pulmonary artery smooth muscle cell proliferation by up-regulation of p27kip¹ via the ERK signal pathway". Chinese Medical Journal. 124 (19): 3098–104.
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