J You1, Z Yue1, S Chen1, Y Chen2, X Lu3, X Zhang1,4, P Shen1, J Li1, Q Han5, Z Li1, P Liu1. 1. Department of Pharmacology and Toxicology, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China. 2. Department of Pharmacy, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China. 3. School of Nursing, Guangdong Pharmaceutical University, Guangzhou, Guangdong, China. 4. School of Medicine, Xizang Minzu University, Xianyang, ShaanXi, China. 5. Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Guangzhou, China.
Abstract
AIM: The transcriptional cofactor receptor-interacting protein 140 (RIP140) is known as a deleterious regulator of cardiac mitochondrial function and energy metabolic homeostasis. This study revealed that RIP140 repressed Sirtuin 3 (SIRT3), a mitochondrial deacetylase that plays an important role in regulating cardiac function. METHODS: RIP140 was overexpressed by adenovirus infection or was knocked down by RNA interference in neonatal rat cardiomyocytes. RESULTS: RIP140 overexpression repressed, while RIP140 silencing elevated the expression and activity of SIRT3. Ad-RIP140 enhanced the expressions of the cardiac hypertrophic markers and increased cardiomyocyte surface area, whereas SIRT3 overexpression prevented the effect of Ad-RIP140. Additionally, SIRT3 overexpression reversed Ad-RIP140-induced mitochondrial dysfunction and energy metabolic dysfunction, such as increase in oxidative stress, decrease in mitochondrial membrane potential and ATP production, as well as downregulation of mitochondrial DNA-encoded genes and genes related to mitochondrial genome replication and transcription, mitochondrial oxidative phosphorylation and fatty acid oxidation. In contrast, SIRT3 silencing exacerbated RIP140-induced cardiomyocyte hypertrophy and mitochondrial dysfunction. Furthermore, the repression of SIRT3 by RIP140 was dependent on estrogen-related receptor-α (ERRα). The involvement of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was ruled out of SIRT3 suppression by RIP140. RIP140 and PGC-1α might act as functional antagonists on the regulation of SIRT3. CONCLUSION: This study indicates that suppression of SIRT3 by RIP140 facilitates the development of cardiomyocyte hypertrophy, mitochondrial dysfunction and energy metabolic dysfunction. Strategies targeting inhibition of RIP140 and upregulation of SIRT3 might improve cardiac energy metabolism and suggest therapeutic potential for heart diseases.
AIM: The transcriptional cofactor receptor-interacting protein 140 (RIP140) is known as a deleterious regulator of cardiac mitochondrial function and energy metabolic homeostasis. This study revealed that RIP140 repressed Sirtuin 3 (SIRT3), a mitochondrial deacetylase that plays an important role in regulating cardiac function. METHODS:RIP140 was overexpressed by adenovirus infection or was knocked down by RNA interference in neonatal rat cardiomyocytes. RESULTS:RIP140 overexpression repressed, while RIP140 silencing elevated the expression and activity of SIRT3. Ad-RIP140 enhanced the expressions of the cardiac hypertrophic markers and increased cardiomyocyte surface area, whereas SIRT3 overexpression prevented the effect of Ad-RIP140. Additionally, SIRT3 overexpression reversed Ad-RIP140-induced mitochondrial dysfunction and energy metabolic dysfunction, such as increase in oxidative stress, decrease in mitochondrial membrane potential and ATP production, as well as downregulation of mitochondrial DNA-encoded genes and genes related to mitochondrial genome replication and transcription, mitochondrial oxidative phosphorylation and fatty acid oxidation. In contrast, SIRT3 silencing exacerbated RIP140-induced cardiomyocyte hypertrophy and mitochondrial dysfunction. Furthermore, the repression of SIRT3 by RIP140 was dependent on estrogen-related receptor-α (ERRα). The involvement of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was ruled out of SIRT3 suppression by RIP140. RIP140 and PGC-1α might act as functional antagonists on the regulation of SIRT3. CONCLUSION: This study indicates that suppression of SIRT3 by RIP140 facilitates the development of cardiomyocyte hypertrophy, mitochondrial dysfunction and energy metabolic dysfunction. Strategies targeting inhibition of RIP140 and upregulation of SIRT3 might improve cardiac energy metabolism and suggest therapeutic potential for heart diseases.
Authors: Melina A Dattilo; Yanina Benzo; Lucía M Herrera; Jesica G Prada; Ana F Castillo; Ulises D Orlando; Ernesto J Podesta; Paula M Maloberti Journal: Sci Rep Date: 2019-07-16 Impact factor: 4.379