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Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide

PURPOSE: Abnormalities of MITO dynamics occur in HF and have been implicated in disease progression. This study describes the broad range abnormalities of mitochondrial (MITO) dynamics in Heart Failure with reduced ejection fraction (HF) and evaluates the effects of long-term therapy with elamipreti...

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Autores principales: Sabbah, Hani N., Gupta, Ramesh C., Singh-Gupta, Vinita, Zhang, Kefei, Lanfear, David E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133191/
https://www.ncbi.nlm.nih.gov/pubmed/29951944
http://dx.doi.org/10.1007/s10557-018-6805-y
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author Sabbah, Hani N.
Gupta, Ramesh C.
Singh-Gupta, Vinita
Zhang, Kefei
Lanfear, David E.
author_facet Sabbah, Hani N.
Gupta, Ramesh C.
Singh-Gupta, Vinita
Zhang, Kefei
Lanfear, David E.
author_sort Sabbah, Hani N.
collection PubMed
description PURPOSE: Abnormalities of MITO dynamics occur in HF and have been implicated in disease progression. This study describes the broad range abnormalities of mitochondrial (MITO) dynamics in Heart Failure with reduced ejection fraction (HF) and evaluates the effects of long-term therapy with elamipretide (ELAM), a MITO-targeting peptide, on these abnormalities. METHODS: Studies were performed in left ventricular tissue from dogs and humans with HF, and were compared with tissue from healthy dogs and healthy donor human hearts. Dogs with HF were randomized to 3 months therapy with ELAM or vehicle. The following were evaluated in dog and human hearts: (1) regulators of MITO biogenesis, including endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α, a transcription factor that drives MITO biogenesis); (2) regulators of MITO fission and fusion, including fission-1, dynamin-related protein-1, mitofusion-2, dominant optic atrophy-1, and mitofilin; and (3) determinants of cardiolipin (CL) synthesis and remodeling, including CL synthase-1, tafazzin-1, and acyl-CoA:lysocardiolipin acyltransferase-1. RESULTS: The study showed decreased levels of eNOS, cGMP, and PGC-1α in HF (dog and human). Increased levels of fission-associated proteins, decreased levels of fusion-associated proteins, decreased mitofilin, and abnormalities of CL synthesis and remodeling were also observed. In all instances, these maladaptations were normalized following long-term therapy with ELAM. CONCLUSIONS: Critical abnormalities of MITO dynamics occur in HF and are normalized following long-term therapy with ELAM. The findings provide support for the continued development of ELAM for the treatment of HF.
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spelling pubmed-61331912018-09-14 Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide Sabbah, Hani N. Gupta, Ramesh C. Singh-Gupta, Vinita Zhang, Kefei Lanfear, David E. Cardiovasc Drugs Ther Original Article PURPOSE: Abnormalities of MITO dynamics occur in HF and have been implicated in disease progression. This study describes the broad range abnormalities of mitochondrial (MITO) dynamics in Heart Failure with reduced ejection fraction (HF) and evaluates the effects of long-term therapy with elamipretide (ELAM), a MITO-targeting peptide, on these abnormalities. METHODS: Studies were performed in left ventricular tissue from dogs and humans with HF, and were compared with tissue from healthy dogs and healthy donor human hearts. Dogs with HF were randomized to 3 months therapy with ELAM or vehicle. The following were evaluated in dog and human hearts: (1) regulators of MITO biogenesis, including endothelial nitric oxide synthase (eNOS), cyclic guanosine monophosphate (cGMP), and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α, a transcription factor that drives MITO biogenesis); (2) regulators of MITO fission and fusion, including fission-1, dynamin-related protein-1, mitofusion-2, dominant optic atrophy-1, and mitofilin; and (3) determinants of cardiolipin (CL) synthesis and remodeling, including CL synthase-1, tafazzin-1, and acyl-CoA:lysocardiolipin acyltransferase-1. RESULTS: The study showed decreased levels of eNOS, cGMP, and PGC-1α in HF (dog and human). Increased levels of fission-associated proteins, decreased levels of fusion-associated proteins, decreased mitofilin, and abnormalities of CL synthesis and remodeling were also observed. In all instances, these maladaptations were normalized following long-term therapy with ELAM. CONCLUSIONS: Critical abnormalities of MITO dynamics occur in HF and are normalized following long-term therapy with ELAM. The findings provide support for the continued development of ELAM for the treatment of HF. Springer US 2018-06-27 2018 /pmc/articles/PMC6133191/ /pubmed/29951944 http://dx.doi.org/10.1007/s10557-018-6805-y Text en © The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Sabbah, Hani N.
Gupta, Ramesh C.
Singh-Gupta, Vinita
Zhang, Kefei
Lanfear, David E.
Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide
title Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide
title_full Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide
title_fullStr Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide
title_full_unstemmed Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide
title_short Abnormalities of Mitochondrial Dynamics in the Failing Heart: Normalization Following Long-Term Therapy with Elamipretide
title_sort abnormalities of mitochondrial dynamics in the failing heart: normalization following long-term therapy with elamipretide
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133191/
https://www.ncbi.nlm.nih.gov/pubmed/29951944
http://dx.doi.org/10.1007/s10557-018-6805-y
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