CaMKIIδC Drives Early Adaptive Ca2+ Change and Late Eccentric Cardiac Hypertrophy.
Circ Res. 2020 Aug 21;:
Authors: Ljubojevic-Holzer S, Herren AW, Djalinac N, Voglhuber J, Morotti S, Holzer M, Wood BM, Abdellatif M, Matzer I, Sacherer M, Radulovic S, Wallner M, Ivanov M, Wagner S, Sossalla S, von Lewinski D, Pieske B, Heller Brown J, Sedej S, Bossuyt J, Bers DM
Rationale: Ca2+-Calmodulin dependent protein kinase (CaMKII) δC activation is implicated in pathological progression of heart failure (HF) and CaMKIIδC transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca2+ handling and CaMKII activation in hypertrophy and HF. Objective: To measure time- and location-dependent activation of CaMKIIδC signaling in adult ventricular cardiomyocytes, during trans-aortic constriction (TAC) and in CaMKIIδC transgenic mice. Methods and Results: We used human tissue from nonfailing and HF hearts, four mouse lines: wild type (WT), CaMKIIδ-knockout (KO), CaMKIIδC transgenic in WT (TG) or KO background and WT mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKIIδC activation and accumulation in nuclear and perinuclear vs. cytosolic regions at 5 days post-TAC. This CaMKIIδ activation caused a compensatory increase in sarcoplasmic reticulum Ca2+ content, Ca2+ transient amplitude and [Ca2+] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKIIδ TG mice (6-8 wk) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11-13 wk, respectively), during which time the compensatory Ca2+ transient effects reversed, but further increases in nuclear and time-averaged [Ca2+] and CaMKII activation occurred. CaMKIIδ TG mice lacking δB exhibited more severe HF, eccentric myocyte growth and nuclear changes. Patient HF samples also showed greatly increased CaMKIIδ expression, especially for CaMKIIδC in nuclear fractions. Conclusions: We conclude that in early TAC perinuclear CaMKIIδC activation promotes adaptive increases in myocyte Ca2+ transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca2+-CaMKIIδC axis contributes to eccentric hypertrophy and HF.
PMID: 32821022 [PubMed – as supplied by publisher]