Autophagy guided interventions to modify the cardiac phenotype of Danon disease.

Autor: Yadin D; Felsenstein Research Center and the Department of Cardiothoracic, Rabin Medical Center, Sackler School of Medicine, Tel-Aviv University, Petach Tikva, Israel; Leviev Heart Center, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Israel., Petrover Z; Felsenstein Research Center and the Department of Cardiothoracic, Rabin Medical Center, Sackler School of Medicine, Tel-Aviv University, Petach Tikva, Israel; Bar-Ilan University, Ramat Gan, Israel., Shainberg A; Bar-Ilan University, Ramat Gan, Israel., Alcalai R; Heart Institute, Hadassah Hebrew University Medical Center, Jerusalem, Israel., Waldman M; Felsenstein Research Center and the Department of Cardiothoracic, Rabin Medical Center, Sackler School of Medicine, Tel-Aviv University, Petach Tikva, Israel., Seidman J; Department of Genetics, Harvard Medical School, Boston, MA, USA., Seidman CE; Department of Genetics, Harvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute and Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, United States., Abraham NG; Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY, USA., Hochhauser E; Felsenstein Research Center and the Department of Cardiothoracic, Rabin Medical Center, Sackler School of Medicine, Tel-Aviv University, Petach Tikva, Israel., Arad M; Leviev Heart Center, Sheba Medical Center, Sackler School of Medicine, Tel-Aviv University, Israel. Electronic address: michael.arad@sheba.health.gov.il.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2022 Oct; Vol. 204, pp. 115229. Date of Electronic Publication: 2022 Aug 24.
DOI: 10.1016/j.bcp.2022.115229
Abstrakt: Danon disease is a lethal X-linked genetic syndrome resulting from radical mutations in the LAMP2 gene. LAMP2 protein deficiency results in defective lysosomal function, autophagy arrest and a multisystem disorder primarily involving the heart, skeletal muscle and the central nervous system. Cardiomyopathy is the main cause of morbidity and mortality. To investigate the mechanisms of and develop therapies for cardiac Danon disease we engineered a mouse model carrying an exon 6 deletion human mutation in LAMP2, which recapitulates the human cardiac disease phenotype. Mice develop cardiac hypertrophy followed by left ventricular dilatation and systolic dysfunction, in association with progressive fibrosis, oxidative stress, accumulation of autophagosomes and activation of proteasome. Stimulation of autophagy in Danon mice (by exercise training, caloric restriction, and rapamycin) aggravate the disease phenotype, promoting dilated cardiomyopathy. Inhibiting autophagy (by high fat diet or hydroxychloroquine) is better tolerated by Danon mice compared to wild type but is not curative. Inhibiting proteasome by Velcade was found to be highly toxic to Danon mice, suggesting that proteasome is activated to compensate for defective autophagy. In conclusion, activation of autophagy should be avoided in Danon patients. Since Danon's is a lifelong disease, we suggest that lifestyle interventions to decrease cardiac stress may be useful to slow progression of Danon's cardiomyopathy. While Danon mice better tolerate high fat diet and sedentary lifestyle, the benefit regarding cardiomyopathy in humans needs to be balanced against other health consequences of such interventions.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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