Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis · 2026
Proteostasis is disrupted in human endothelial cells by serum from ATTR patients and is rescued by tafamidis treatment.
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Gianniou Despoina D, Delialis Dimitrios, Georgiopoulos Georgios, Bampatsias Dimitrios, Gkogkou Eirini, Theodorakakou Foteini, Nikolaou Panagiota Efstathia, Choustoulaki Angeliki, Briasoulis Alexandros, Petropoulos Ioannis, Papanagnou Eleni-Dimitra, Dimoula Anna, Courraud Julie, Patras Raphael, Soranidis Angelos, Dimopoulos Meletios-Athanasios, Trougakos Ioannis P, Kastritis Efstathios, Stamatelopoulos Kimon
Аннотация
BACKGROUND: The vascular effects of wild-type (ATTRwt-CM) and hereditary (ATTRv-CM) transthyretin cardiac amyloidosis, and the impact of tafamidis treatment, remain unclear.
METHODS: Serum from ATTRwt-CM and ATTRv-CM patients (pre- and 6-months post-Tafamidis treatment) elderly and young controls, was applied on human umbilical vein endothelial cells (HUVECs). Viability, motility, and stress responses and serum cytokine and proteomic profiles were assessed. Recombinant TTR, with and without tafamidis co-treatment, were also evaluated. Pulse wave velocity (PWV) was longitudinally assessed in ATTRwt-CM patients pre- and post-tafamidis treatment and in elderly controls.
RESULTS: ATTRwt-CM or ATTRv serum reduced HUVECs viability and motility, inducing proteotoxic and oxidative stress, while serum cytokine and proteome profiling revealed inflammatory-related signatures; All these effects were attenuated in HUVECs treated with post-Tafamidis serum. Recombinant TTR also induced proteotoxic stress, which was attenuated by tafamidis co-treatment (safety range ≤ 16 μM). Consistently, PWV was reduced in ATTRwt-CM patients after Tafamidis, as compared to controls, correlating with increased serum transthyretin and reduced PBMCs' proteasome activity.
CONCLUSIONS: Serum from ATTR-CM patients or recombinant TTR directly induced toxic effects in HUVECs. Tafamidis mitigated these effects in vitro and improved arterial stiffness in ATTRwt-CM patients, implying protective vascular effects of tafamidis in ATTR-CM beyond direct myocardial transthyretin stabilization.
METHODS: Serum from ATTRwt-CM and ATTRv-CM patients (pre- and 6-months post-Tafamidis treatment) elderly and young controls, was applied on human umbilical vein endothelial cells (HUVECs). Viability, motility, and stress responses and serum cytokine and proteomic profiles were assessed. Recombinant TTR, with and without tafamidis co-treatment, were also evaluated. Pulse wave velocity (PWV) was longitudinally assessed in ATTRwt-CM patients pre- and post-tafamidis treatment and in elderly controls.
RESULTS: ATTRwt-CM or ATTRv serum reduced HUVECs viability and motility, inducing proteotoxic and oxidative stress, while serum cytokine and proteome profiling revealed inflammatory-related signatures; All these effects were attenuated in HUVECs treated with post-Tafamidis serum. Recombinant TTR also induced proteotoxic stress, which was attenuated by tafamidis co-treatment (safety range ≤ 16 μM). Consistently, PWV was reduced in ATTRwt-CM patients after Tafamidis, as compared to controls, correlating with increased serum transthyretin and reduced PBMCs' proteasome activity.
CONCLUSIONS: Serum from ATTR-CM patients or recombinant TTR directly induced toxic effects in HUVECs. Tafamidis mitigated these effects in vitro and improved arterial stiffness in ATTRwt-CM patients, implying protective vascular effects of tafamidis in ATTR-CM beyond direct myocardial transthyretin stabilization.