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Unveiling myosin dysfunction in Hypertrophic Cardiomyopathy
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Resumo(s)
Hypertrophic cardiomyopathy (HCM) is the most prevalent cardiac genetic disease, often
leading to early sudden cardiac death, affecting more than 1 in 500 people worldwide. This
condition is characterized by a thickened left ventricular wall, resulting in reduced blood supply
to the body and elevated pressure in the left atrium. Half of HCM cases are caused by mutations
in genes encoding sarcomeric proteins (sarcomere mutation-positive cases - SMP), and the other
half cases have unidentified causes (sarcomere mutation-negative cases - SMN).
Molecular features of SMP-HCM include hyper-contractility as attested by an excess
myosin cross-bridge formation and dysregulation of myosin super-relaxed state (SRX).
Mavacamten (MYK-461), a small molecule that lowers hyper-contractility by inhibiting
myosin ATPase activity, has been proven efficient in SMP-HCM. It reduces myosin cross-bridge
numbers and promotes myosin SRX state.
The aim of this dissertation was to analyse if the SRX-DRX equilibrium was altered,
thereby leading to an over-consumption of ATP, in samples from SMP and SMN patients with
HCM and to investigate if the addition of MYK-461 restores de SRX-DRX equilibrium.
Myectomy samples from SMP-HCM patients, SMN-HCM patients, and healthy donors
were used. The MANT-ATP chase experiment was applied with and without MYK-461 to
measure the myosin turnover.
The results showed a significant difference in P1 and P2 between the groups of samples
(SMP, SMN and donors), but not between treatment with MYK-4611. However, SMP patients
tend to have a higher P1 compared to donors or patients with SMN mutations. Treatment with
MYK-461 tended to lower P1 and increase P2 for SMP patients in contrast to donors and patients
with SMN mutations. From these results can it be concluded that MYK-461 did not make a
substantial difference.
A small sample size might be the cause, thus more myectomy samples need to be
analyzed.
Descrição
Tese de mestrado, Biologia Humana e Ambiente, 2023, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Cardiomiopatia hipertrófica (CMH) Mavacamten (MYK-461) Mutação Sarcomérica Positiva (MSP) Mutação Sarcomérica Negativa (MSN) Miosina Teses de mestrado - 2024