Journal of molecular and cellular cardiology plus · 2025
Persistently increased CaMKIIδ autophosphorylation mediates pathologic SR Ca loss in a murine model of Doxorubicin-induced cardiomyopathy.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Feder Anna-Lena, Tarnowski Daniel, Pfützenreuter Anna-Maria, Baier Maria Johanna, Mustroph Julian, Nanadikar Maithily S, Katschinski Dörthe M, Maier Lars Siegfried, Sag Can Martin
Аннотация
BACKGROUND: Doxorubicin (DOX)-induced cardiomyopathy (DICM) manifests as left ventricular (LV) systolic dysfunction. DOX triggers oxidative stress and CaMKIIδ activity in cardiac myocytes. CaMKIIδ activation leads to impaired intracellular Ca handling and contractile dysfunction because of pathologic Ca loss from the sarcoplasmic reticulum (SR). While CaMKIIδ is canonically activated by autophosphorylation, it can also be activated via oxidation.
OBJECTIVES: We aimed to investigate the predominant mode of CaMKIIδ activation in DICM.
METHODS: We utilized two transgenic mouse models, one lacking CaMKIIδ (CaMKIIδ-/-) and a "redox-dead" CaMKIIδVal281/282 model. Acute changes in intracellular Ca handling and CaMKIIδ activation status were examined following 15 min of DOX exposure. Long-term effects were studied in CaMKIIδ-/- mice (vs. CaMKIIδ+/+ wildtype littermates) and redox-dead CaMKIIδVal281/282 mice (vs. CaMKIIδMet281/282 wildtype littermates) that underwent DOX treatment in-vivo. Cardiac function (via echocardiography), intracellular Ca handling, and CaMKIIδ-related signaling were assessed 12 weeks post-treatment.
RESULTS: DOX acutely increased CaMKIIδ activity by autophosphorylation and oxidation in both WT lines, while autophosphorylated CaMKIIδ was still detected in CaMKIIδVal281/282 mice, which resulted in comparably increased SR Ca leakage mediated by CaMKII-dependent RyR2-hyperphosphorylation at pS2814 in all aforementioned groups. In contrast, pharmacological and genetic inhibition of CaMKIIδ (i.e. in CaMKIIδ-/-) prevented DOX-induced CaMKIIδ-hyperactivation, RyR2-hyperphosphorylation and SR Ca loss. Similarly, only CaMKIIδ-/- mice were protected from long-term DOX-induced LV dysfunction in-vivo. Redox-dead CaMKIIδVal281/282 mice exhibited similar LV dysfunction as WT littermates, with persistent CaMKIIδ autophosphorylation, subsequent RyR2 hyperphosphorylation, and increased CaMKIIδ-dependent SR Ca leakage.
CONCLUSIONS: Persistently increased CaMKIIδ autophosphorylation, but not oxidation, mediates pathologic SR Ca loss in Doxorubicin-induced cardiomyopathy.
OBJECTIVES: We aimed to investigate the predominant mode of CaMKIIδ activation in DICM.
METHODS: We utilized two transgenic mouse models, one lacking CaMKIIδ (CaMKIIδ-/-) and a "redox-dead" CaMKIIδVal281/282 model. Acute changes in intracellular Ca handling and CaMKIIδ activation status were examined following 15 min of DOX exposure. Long-term effects were studied in CaMKIIδ-/- mice (vs. CaMKIIδ+/+ wildtype littermates) and redox-dead CaMKIIδVal281/282 mice (vs. CaMKIIδMet281/282 wildtype littermates) that underwent DOX treatment in-vivo. Cardiac function (via echocardiography), intracellular Ca handling, and CaMKIIδ-related signaling were assessed 12 weeks post-treatment.
RESULTS: DOX acutely increased CaMKIIδ activity by autophosphorylation and oxidation in both WT lines, while autophosphorylated CaMKIIδ was still detected in CaMKIIδVal281/282 mice, which resulted in comparably increased SR Ca leakage mediated by CaMKII-dependent RyR2-hyperphosphorylation at pS2814 in all aforementioned groups. In contrast, pharmacological and genetic inhibition of CaMKIIδ (i.e. in CaMKIIδ-/-) prevented DOX-induced CaMKIIδ-hyperactivation, RyR2-hyperphosphorylation and SR Ca loss. Similarly, only CaMKIIδ-/- mice were protected from long-term DOX-induced LV dysfunction in-vivo. Redox-dead CaMKIIδVal281/282 mice exhibited similar LV dysfunction as WT littermates, with persistent CaMKIIδ autophosphorylation, subsequent RyR2 hyperphosphorylation, and increased CaMKIIδ-dependent SR Ca leakage.
CONCLUSIONS: Persistently increased CaMKIIδ autophosphorylation, but not oxidation, mediates pathologic SR Ca loss in Doxorubicin-induced cardiomyopathy.