Lomerizine may ease vascular symptoms in Fabry: Mouse model
Calcium channel blocker seen to improve endothelial cell health, function
Lomerizine — used clinically to treat migraines — helped ease vascular-related symptoms in a mouse model of Fabry disease, according to a new study from researchers in South Korea.
The drug, one of a class of medications called calcium channel blockers, which work to lower blood pressure, also improved the health and function of endothelial cells derived from people with Fabry. Endothelial cells line blood vessels, and play a key role in regulating blood flow.
The researchers found that lomerizine treatment improved the ability of endothelial cells to form new blood vessels, and also blocked mechanisms involved in the dysfunction of these cells. In the mice, lomerizine eased heart and kidney issues and improved heat tolerance and sweating.
“In this study, we present preliminary evidence suggesting lomerizine’s potential for alleviating symptoms in [Fabry disease] patients,” researchers wrote. “However, further investigations are needed to assess its translational applicability as a candidate for [Fabry] therapy.”
The study, “Therapeutic effects of lomerizine on vasculopathy in Fabry disease,” was published in the journal Scientific Reports.
Mouse model mimics vascular disease symptoms seen in Fabry patients
Fabry disease is caused by mutations in the GLA gene that result in the loss of a functional alpha-galactosidase A, or alpha-Gal A, enzyme. That, in turn, leads to the toxic accumulation of fatty molecules like globotriaosylceramide, called Gb3, in several cell types. Endothelial cells, the cells that line the inside of blood vessels, are particularly affected.
Fabry patients often experience vascular lesions in the skin, known as angiokeratomas, and may develop life-threatening conditions related to dysfunction in small blood vessels. Among such conditions are enlargement of the left ventricle — the heart chamber responsible for pumping oxygen-rich blood out to the body — kidney failure, and age-related brain strokes.
In an earlier screening study, lomerizine, a compound that blocks certain types of calcium channels, was found to improve the function of vascular endothelial cells. Lomerizine is used clinically for the treatment of neurological pain, such as migraine, a type of severe headache.
In that study, researchers used induced pluripotent stem cells, or iPSCs, obtained from fully mature skin cells programmed back to a stem cell-like state, which were differentiated into endothelial cells.
Here, using the same cellular model, the team found lomerizine increased the ability of endothelial cells to form new blood vessels — a process known as angiogenesis — in cells derived from patients with different GLA mutations, as compared with nontreated cells. Additionally, lomerizine decreased the levels of anti-angiogenic molecules (pSMAD2 and TSP1) and increased the levels of angiogenic factors (KDR and eNOS) in patient-derived endothelial cells.
Lomerizine also reduced the accumulation of calcium inside mitochondria, the cellular compartments that produce the energy cells need to function. Further, treatment lessened the formation of reactive oxygen species, known to contribute to endothelial cell dysfunction in Fabry disease.
Our results suggest lomerizine as a novel candidate for [Fabry] therapy.
Further analysis indicated that lomerizine decreased a process known as endothelial-to-mesenchymal transition, or EndMT. This process causes endothelial cells to change into a different type of cell that doesn’t support healthy blood flow. EndMT is known to play a role in vascular dysfunction in Fabry disease.
“Together, our results demonstrate that lomerizine suppresses EndMT in [Fabry-derived endothelial cells], thereby improving their angiogenic activity,” the researchers wrote.
The team then tested the efficacy of lomerizine in a mouse model of Fabry, which mimics vascular disease in patients. The treatment was administered orally to the animals, daily for six months, at two doses: 10 or 30 mg/kg/daily. It did not lead to significant systemic adverse effects, the researchers noted.
The Fabry mice displayed an enlargement of the heart’s left ventricle and impaired heart function. In mice treated with lomerizine, left ventricle size decreased and heart function improved. Other disease symptoms, including reduced sweating and heat intolerance, and fibrosis and inflammation of vascular endothelial cells in the kidney, also improved with the treatment.
“This series of biochemical changes triggered by lomerizine in [vascular endothelial cells] suggests its potential to mitigate key pathological features of [Fabry disease],” the researchers wrote. “Thus, our results suggest lomerizine as a novel candidate for [Fabry] therapy.”
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