Plekhm2 acts as an autophagy modulator in murine heart and cardiofibroblasts.

Autor: Etzion S; Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, P.O. Box 653, 84105, Be'er-Sheva, Israel. shar@bgu.ac.il., Hijaze R; Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, P.O. Box 653, 84105, Be'er-Sheva, Israel.; Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84101, Be'er-Sheva, Israel., Segal L; Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, P.O. Box 653, 84105, Be'er-Sheva, Israel.; Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84101, Be'er-Sheva, Israel., Pilcha S; Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, P.O. Box 653, 84105, Be'er-Sheva, Israel., Masil D; Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, P.O. Box 653, 84105, Be'er-Sheva, Israel.; Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84101, Be'er-Sheva, Israel., Levi O; Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, P.O. Box 653, 84105, Be'er-Sheva, Israel.; Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84101, Be'er-Sheva, Israel., Elyagon S; Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, P.O. Box 653, 84105, Be'er-Sheva, Israel.; Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84101, Be'er-Sheva, Israel., Levitas A; Department of Pediatric Cardiology, Soroka University Medical Center, Ben-Gurion University of the Negev, 84101, Be'er-Sheva, Israel., Etzion Y; Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, P.O. Box 653, 84105, Be'er-Sheva, Israel.; Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84101, Be'er-Sheva, Israel., Parvari R; Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, 84101, Be'er-Sheva, Israel.; National Institute for Biotechnology, Ben-Gurion University of the Negev, 84101, Be'er-Sheva, Israel.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Jun 28; Vol. 14 (1), pp. 14949. Date of Electronic Publication: 2024 Jun 28.
DOI: 10.1038/s41598-024-65670-5
Abstrakt: Plekhm2 is a protein regulating endosomal trafficking and lysosomal distribution. We recently linked a recessive inherited mutation in PLEKHM2 to a familial form of dilated cardiomyopathy and left ventricular non-compaction. These patients' primary fibroblasts exhibited abnormal lysosomal distribution and autophagy impairment. We therefore hypothesized that loss of PLEKHM2 impairs cardiac function via autophagy derangement. Here, we characterized the roles of Plekhm2 in the heart using global Plekhm2 knockout (PLK2-KO) mice and cultured cardiac cells. Compared to littermate controls (WT), young PLK2-KO mice exhibited no difference in heart function or autophagy markers but demonstrated higher basal AKT phosphorylation. Older PLK2-KO mice had body and heart growth retardation and increased LC3II protein levels. PLK2-KO mice were more vulnerable to fasting and, interestingly, impaired autophagy was noted in vitro, in Plekhm2-deficient cardiofibroblasts but not in cardiomyocytes. PLK2-KO hearts appeared to be less sensitive to pathological hypertrophy induced by angiotensin-II compared to WT. Our findings suggest a role of Plekhm2 in murine cardiac autophagy. Plekhm2 deficiency impaired autophagy in cardiofibroblasts, but the autophagy in cardiomyocytes is not critically dependent on Plekhm2. The absence of Plekhm2 in mice appears to promote compensatory mechanism(s) enabling the heart to manage angiotensin-II-induced stress without detrimental consequences.
(© 2024. The Author(s).)
Databáze: MEDLINE
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