Life sciences · 2020
Relative role of T-tubules disruption and decreased SERCA2 on contractile dynamics of isolated rat ventricular myocytes.
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Celestino-Montes Antonio, Pérez-Treviño Perla, Sandoval-Herrera Maya D, Gómez-Víquez Norma L, Altamirano Julio
Аннотация
AIMS: Ventricular myocytes (VM) depolarization activates L-type Ca2+ channels (LCC) allowing Ca2+ influx (ICa) to synchronize sarcoplasmic reticulum (SR) Ca2+ release, via Ca2+-release channels (RyR2). The resulting whole-cell Ca2+ transient triggers contraction, while cytosolic Ca2+ removal by SR Ca2+ pump (SERCA2) and sarcolemmal Na+/Ca2+ exchanger (NCX) allows relaxation. In diseased hearts, extensive VM remodeling causes heterogeneous, blunted and slow Ca2+ transients. Among remodeling changes are: A) T-tubules disorganization. B) Diminished SERCA2 and low SR Ca2+. However, those often overlap, hindering their relative contribution to contractile dysfunction (CD). Furthermore, few studies have assessed their specific impact on the spatiotemporal Ca2+ transient properties and contractile dynamics simultaneously. Therefore, we sought to perform a quantitative comparison of how heterogeneous and slow Ca2+ transients, with different underlying determinants, affect contractile performance.
METHODS: We used two experimental models: A) formamide-induced acute "detubulation", where VM retain functional RyR2 and SERCA2, but lack T-tubules-associated LCC and NCX. B) Intact VM from hypothyroid rats, presenting decreased SERCA2 and SR Ca2+, but maintained T-tubules. By confocal imaging of Fluo-4-loaded VM, under field-stimulation, simultaneously acquired Ca2+ transients and shortening, allowing direct correlations.
KEY FINDINGS: We found near-linear correlations among key parameters of altered Ca2+ transients, caused independently by T-tubules disruption or decreased SR Ca2+, and shortening and relaxation, SIGNIFICANCE: Unrelated structural and molecular alterations converge in similarly abnormal Ca2+ transients and CD, highlighting the importance of independently reproduce disease-specific alterations, to quantitatively assess their impact on Ca2+ signaling and contractility, which would be valuable to determine potential disease-specific therapeutic targets.
METHODS: We used two experimental models: A) formamide-induced acute "detubulation", where VM retain functional RyR2 and SERCA2, but lack T-tubules-associated LCC and NCX. B) Intact VM from hypothyroid rats, presenting decreased SERCA2 and SR Ca2+, but maintained T-tubules. By confocal imaging of Fluo-4-loaded VM, under field-stimulation, simultaneously acquired Ca2+ transients and shortening, allowing direct correlations.
KEY FINDINGS: We found near-linear correlations among key parameters of altered Ca2+ transients, caused independently by T-tubules disruption or decreased SR Ca2+, and shortening and relaxation, SIGNIFICANCE: Unrelated structural and molecular alterations converge in similarly abnormal Ca2+ transients and CD, highlighting the importance of independently reproduce disease-specific alterations, to quantitatively assess their impact on Ca2+ signaling and contractility, which would be valuable to determine potential disease-specific therapeutic targets.