Publicação
Unveiling myosin dysfunction in Hypertrophic Cardiomyopathy
| datacite.subject.fos | Departamento de Biologia Animal | pt_PT |
| dc.contributor.advisor | Ochala, Julien | |
| dc.contributor.advisor | Rebelo, Maria Teresa Ferreira Ramos Nabais de Oliveira, 1964- | |
| dc.contributor.author | Cruz, Débora Trogeira | |
| dc.date.accessioned | 2024-02-21T15:36:27Z | |
| dc.date.available | 2024-02-21T15:36:27Z | |
| dc.date.issued | 2024 | |
| dc.date.submitted | 2023 | |
| dc.description | Tese de mestrado, Biologia Humana e Ambiente, 2023, Universidade de Lisboa, Faculdade de Ciências | pt_PT |
| dc.description.abstract | 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. | pt_PT |
| dc.identifier.tid | 203881532 | |
| dc.identifier.uri | http://hdl.handle.net/10451/62775 | |
| dc.language.iso | eng | pt_PT |
| dc.subject | Cardiomiopatia hipertrófica (CMH) | pt_PT |
| dc.subject | Mavacamten (MYK-461) | pt_PT |
| dc.subject | Mutação Sarcomérica Positiva (MSP) | pt_PT |
| dc.subject | Mutação Sarcomérica Negativa (MSN) | pt_PT |
| dc.subject | Miosina | pt_PT |
| dc.subject | Teses de mestrado - 2024 | pt_PT |
| dc.title | Unveiling myosin dysfunction in Hypertrophic Cardiomyopathy | pt_PT |
| dc.type | master thesis | |
| dspace.entity.type | Publication | |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | masterThesis | pt_PT |
| thesis.degree.name | Tese de mestrado em Biologia Humana e Ambiente | pt_PT |