title: Heart-specific Rpd3 downregulation enhances cardiac function and longevity.
abstract: Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan in Drosophila melanogaster. Once revealed that long-lived fruit flies exhibit limited cardiac decline, we investigated whether Rpd3 downregulation would improve stress resistance and/or lifespan when targeted in the heart. Contested against three different stressors (oxidation, starvation and heat), heart-specific Rpd3 downregulation significantly enhanced stress resistance in flies. However, these higher levels of resistance were not observed when Rpd3 downregulation was targeted in other tissues or when other long-lived flies were tested in the heart-specific manner. Interestingly, the expressions of anti-aging genes such as sod2, foxo and Thor, were systemically increased as a consequence of heart-specific Rpd3 downregulation. Showing higher resistance to oxidative stress, the heart-specific Rpd3 downregulation concurrently exhibited improved cardiac functions, demonstrating an increased heart rate, decreased heart failure and accelerated heart recovery. Conversely, Rpd3 upregulation in cardiac tissue reduced systemic resistance against heat stress with decreased heart function, also specifying phosphorylated Rpd3 levels as a significant modulator. Continual downregulation of Rpd3 throughout aging increased lifespan, implicating that Rpd3 deacetylase in the heart plays a significant role in cardiac function and longevity to systemically modulate the fly's response to the environment.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Kopp
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Jo-Lin
authors.initials: JL
authors.lastname: Hsieh
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: William
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Dhelni T
authors.initials: DT
authors.lastname: Bhatt
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Sae Yeon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fan
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Veevek
authors.initials: V
authors.lastname: Shah
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Emaad
authors.initials: E
authors.lastname: Siddiqui
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Ragam
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Dev
authors.initials: D
authors.lastname: Ardeshna
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Kunwoo
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Hardik
authors.initials: H
authors.lastname: Parikh
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Ayush
authors.initials: A
authors.lastname: Parikh
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Yuh-Ru
authors.initials: YR
authors.lastname: Lin
authors.affiliation: Department of Cell Biology and Molecular Medicine, Rutgers-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Yongkyu
authors.initials: Y
authors.lastname: Park
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000096:biosynthesis* / Q000235:genetics*; D004331:Drosophila melanogaster; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000453:epidemiology / Q000235:genetics; D006339:Heart Rate / Q000235:genetics; D018882:Heat Stress Disorders / Q000235:genetics / Q000503:physiopathology; D056284:Histone Deacetylase 1 / Q000096:biosynthesis* / Q000235:genetics*; D008136:Longevity / Q000235:genetics* / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress; D010766:Phosphorylation
chemical_list: D029721:Drosophila Proteins; C512966:HDAC1 protein, Drosophila; D056284:Histone Deacetylase 1
keywords: Rpd3, cardiac function; aging; gene expression; stress resistance