Transcriptional regulation profiling reveals PPARA-mediated fatty acid oxidation as a novel therapeutic target in phospholamban R14del cardiomyopathy-Reference-Cited by-同舟云学术

Transcriptional regulation profiling reveals PPARA-mediated fatty acid oxidation as a novel therapeutic target in phospholamban R14del cardiomyopathy

Published:2022-10-28 Issue: Volume: Page:
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Author:

Harakalova Magdalena¹^ORCID,Pei Jiayi¹,Maas Renee¹,Gaar-Humphreys Karen¹,Gho Johannes¹,Nagyova Emilia¹,Blok Christian Snijders¹,Adrichem Iris van¹,Es René van¹,Sepehrkhouy Shahrzad¹,Feyen Dries²,Dungen Noortje van den³,Lansu Nico¹,Calis Jorg¹,Kaaij Niels van der¹^ORCID,de Jonge Nicolaas¹,Laake Linda van¹,Riele Anneline ter⁴,Huibers Manon¹,de Weger Roel¹,Verhaar Marianne C.³^ORCID,Tintelen J. Peter van⁵^ORCID,Vaz Frederic⁶^ORCID,Burgering Boudewijn⁷,Mil Alain van¹,Buikema Jan¹,Vink Aryan¹^ORCID,Karakikes Ioannis²,Mercola Mark²^ORCID,Doevendans Pieter AFM¹^ORCID,Sluijter Joost¹,Steenbeek Frank van¹,Cheng Caroline¹,Mokry Michal¹^ORCID,Asselbergs Folkert¹^ORCID

Affiliation:

1. University Medical Center Utrecht

2. Stanford University

3. UMC Utrecht

4. UMCU

5. University Medical Center Utrecht, University of Utrecht

6. . Department of Clinical Chemistry, Amsterdam Gastroenterology & Metabolism, Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam

7. Uni

Abstract

Abstract Carriers of the R14del pathogenic variant in the phospholamban (PLN) gene develop severe cardiomyopathy with extracellular adipocyte infiltration and intracellular cardiomyocyte mitochondrial disturbances. However, the basis of this metabolic dysregulation tailoring potential treatment targets is unknown. Here, we present a combined approach of transcriptional regulation analysis in human primary tissue and validation in a unique long-term (160 days) matured human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model. We demonstrate a dysregulated PPARA-mediated mitochondrial fatty acid oxidation (FAO) signalling in PLN-R14del hearts and hiPSC-CMs. PLN-R14del hiPSC-CMs also displayed a higher preference for glycolysis over FAO and presented limited flexibility in energy substrate switching leading to enhanced lipid droplet storage. By activating PPARA in PLN-R14del hiPSC-CMs using bezafibrate, we observed an improved mitochondrial structure and calcium handling function, further indicating the importance of FAO in the disease and the potential of PPARA agonists as a novel therapeutic strategy in cardiomyopathies.

Publisher

Research Square Platform LLC

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