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- Title
Upregulation of Rubicon promotes autosis during myocardial ischemia/reperfusion injury.
- Authors
Nah, Jihoon; Peiyong Zhai; Chun-Yang Huang; Fernández, Álvaro F.; Mareedu, Satvik; Levine, Beth; Junichi Sadoshima; Zhai, Peiyong; Huang, Chun-Yang; Sadoshima, Junichi
- Abstract
Although autophagy is generally protective, uncontrolled or excessive activation of autophagy can be detrimental. However, it is often difficult to distinguish death by autophagy from death with autophagy, and whether autophagy contributes to death in cardiomyocytes (CMs) is still controversial. Excessive activation of autophagy induces a morphologically and biochemically defined form of cell death termed autosis. Whether autosis is involved in tissue injury induced under pathologically relevant conditions is poorly understood. In the present study, myocardial ischemia/reperfusion (I/R) induced autosis in CMs, as evidenced by cell death with numerous vacuoles and perinuclear spaces, and depleted intracellular membranes. Autosis was observed frequently after 6 hours of reperfusion, accompanied by upregulation of Rubicon, attenuation of autophagic flux, and marked accumulation of autophagosomes. Genetic downregulation of Rubicon inhibited autosis and reduced I/R injury, whereas stimulation of autosis during the late phase of I/R with Tat-Beclin 1 exacerbated injury. Suppression of autosis by ouabain, a cardiac glycoside, in humanized Na+,K+-ATPase-knockin mice reduced I/R injury. Taken together, these results demonstrate that autosis is significantly involved in I/R injury in the heart and triggered by dysregulated accumulation of autophagosomes due to upregulation of Rubicon.
- Subjects
CORONARY disease; REPERFUSION injury; GENETIC regulation; INTRACELLULAR membranes; HEART injuries
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 6, p2978
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI132366