Hypercholesterolemia downregulates autophagy in the rat heart

Z. Giricz, Gábor Koncsos, Tomáš Rajtík, Zoltán V. Varga, Tamás Baranyai, C. Csonka, Adrián Szobi, Adriana Adameová, Roberta A. Gottlieb, Péter Ferdinandy

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: We have previously shown that efficiency of ischemic conditioning is diminished in hypercholesterolemia and that autophagy is necessary for cardioprotection. However, it is unknown whether isolated hypercholesterolemia disturbs autophagy or the mammalian target of rapamycin (mTOR) pathways. Therefore, we investigated whether isolated hypercholesterolemia modulates cardiac autophagy-related pathways or programmed cell death mechanisms such as apoptosis and necroptosis in rat heart. Methods: Male Wistar rats were fed either normal chow (NORM; n = 9) or with 2% cholesterol and 0.25% cholic acid-enriched diet (CHOL; n = 9) for 12 weeks. CHOL rats exhibited a 41% increase in plasma total cholesterol level over that of NORM rats (4.09 mmol/L vs. 2.89 mmol/L) at the end of diet period. Animals were sacrificed, hearts were excised and briefly washed out. Left ventricles were snap-frozen for determination of markers of autophagy, mTOR pathway, apoptosis, and necroptosis by Western blot. Results: Isolated hypercholesterolemia was associated with a significant reduction in expression of cardiac autophagy markers such as LC3-II, Beclin-1, Rubicon and RAB7 as compared to controls. Phosphorylation of ribosomal S6, a surrogate marker for mTOR activity, was increased in CHOL samples. Cleaved caspase-3, a marker of apoptosis, increased in CHOL hearts, while no difference in the expression of necroptotic marker RIP1, RIP3 and MLKL was detected between treatments. Conclusions: This is the first comprehensive analysis of autophagy and programmed cell death pathways of apoptosis and necroptosis in hearts of hypercholesterolemic rats. Our data show that isolated hypercholesterolemia suppresses basal cardiac autophagy and that the decrease in autophagy may be a result of an activated mTOR pathway. Reduced autophagy was accompanied by increased apoptosis, while cardiac necroptosis was not modulated by isolated hypercholesterolemia. Decreased basal autophagy and elevated apoptosis may be responsible for the loss of cardioprotection reported in hypercholesterolemic animals.

Original languageEnglish
Article number60
JournalLipids in Health and Disease
Volume16
Issue number1
DOIs
Publication statusPublished - Mar 23 2017

Fingerprint

Autophagy
Hypercholesterolemia
Rats
Down-Regulation
Sirolimus
Apoptosis
Cell death
Nutrition
Animals
Cholesterol
Cholic Acid
Phosphorylation
Cell Death
Caspase 3
Diet
S 6
Plasmas
Heart Ventricles
Wistar Rats
Biomarkers

Keywords

  • Apoptosis
  • ATG8
  • Autophagy
  • Caspase
  • Hypercholesterolemia
  • Necroptosis
  • Programmed necrosis
  • Receptor-interacting serine/threonine-protein kinase

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Hypercholesterolemia downregulates autophagy in the rat heart. / Giricz, Z.; Koncsos, Gábor; Rajtík, Tomáš; Varga, Zoltán V.; Baranyai, Tamás; Csonka, C.; Szobi, Adrián; Adameová, Adriana; Gottlieb, Roberta A.; Ferdinandy, Péter.

In: Lipids in Health and Disease, Vol. 16, No. 1, 60, 23.03.2017.

Research output: Contribution to journalArticle

Giricz, Z, Koncsos, G, Rajtík, T, Varga, ZV, Baranyai, T, Csonka, C, Szobi, A, Adameová, A, Gottlieb, RA & Ferdinandy, P 2017, 'Hypercholesterolemia downregulates autophagy in the rat heart', Lipids in Health and Disease, vol. 16, no. 1, 60. https://doi.org/10.1186/s12944-017-0455-0
Giricz, Z. ; Koncsos, Gábor ; Rajtík, Tomáš ; Varga, Zoltán V. ; Baranyai, Tamás ; Csonka, C. ; Szobi, Adrián ; Adameová, Adriana ; Gottlieb, Roberta A. ; Ferdinandy, Péter. / Hypercholesterolemia downregulates autophagy in the rat heart. In: Lipids in Health and Disease. 2017 ; Vol. 16, No. 1.
@article{662a37041afc436b87493cb72c5eaaf2,
title = "Hypercholesterolemia downregulates autophagy in the rat heart",
abstract = "Background: We have previously shown that efficiency of ischemic conditioning is diminished in hypercholesterolemia and that autophagy is necessary for cardioprotection. However, it is unknown whether isolated hypercholesterolemia disturbs autophagy or the mammalian target of rapamycin (mTOR) pathways. Therefore, we investigated whether isolated hypercholesterolemia modulates cardiac autophagy-related pathways or programmed cell death mechanisms such as apoptosis and necroptosis in rat heart. Methods: Male Wistar rats were fed either normal chow (NORM; n = 9) or with 2{\%} cholesterol and 0.25{\%} cholic acid-enriched diet (CHOL; n = 9) for 12 weeks. CHOL rats exhibited a 41{\%} increase in plasma total cholesterol level over that of NORM rats (4.09 mmol/L vs. 2.89 mmol/L) at the end of diet period. Animals were sacrificed, hearts were excised and briefly washed out. Left ventricles were snap-frozen for determination of markers of autophagy, mTOR pathway, apoptosis, and necroptosis by Western blot. Results: Isolated hypercholesterolemia was associated with a significant reduction in expression of cardiac autophagy markers such as LC3-II, Beclin-1, Rubicon and RAB7 as compared to controls. Phosphorylation of ribosomal S6, a surrogate marker for mTOR activity, was increased in CHOL samples. Cleaved caspase-3, a marker of apoptosis, increased in CHOL hearts, while no difference in the expression of necroptotic marker RIP1, RIP3 and MLKL was detected between treatments. Conclusions: This is the first comprehensive analysis of autophagy and programmed cell death pathways of apoptosis and necroptosis in hearts of hypercholesterolemic rats. Our data show that isolated hypercholesterolemia suppresses basal cardiac autophagy and that the decrease in autophagy may be a result of an activated mTOR pathway. Reduced autophagy was accompanied by increased apoptosis, while cardiac necroptosis was not modulated by isolated hypercholesterolemia. Decreased basal autophagy and elevated apoptosis may be responsible for the loss of cardioprotection reported in hypercholesterolemic animals.",
keywords = "Apoptosis, ATG8, Autophagy, Caspase, Hypercholesterolemia, Necroptosis, Programmed necrosis, Receptor-interacting serine/threonine-protein kinase",
author = "Z. Giricz and G{\'a}bor Koncsos and Tom{\'a}š Rajt{\'i}k and Varga, {Zolt{\'a}n V.} and Tam{\'a}s Baranyai and C. Csonka and Adri{\'a}n Szobi and Adriana Adameov{\'a} and Gottlieb, {Roberta A.} and P{\'e}ter Ferdinandy",
year = "2017",
month = "3",
day = "23",
doi = "10.1186/s12944-017-0455-0",
language = "English",
volume = "16",
journal = "Lipids in Health and Disease",
issn = "1476-511X",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Hypercholesterolemia downregulates autophagy in the rat heart

AU - Giricz, Z.

AU - Koncsos, Gábor

AU - Rajtík, Tomáš

AU - Varga, Zoltán V.

AU - Baranyai, Tamás

AU - Csonka, C.

AU - Szobi, Adrián

AU - Adameová, Adriana

AU - Gottlieb, Roberta A.

AU - Ferdinandy, Péter

PY - 2017/3/23

Y1 - 2017/3/23

N2 - Background: We have previously shown that efficiency of ischemic conditioning is diminished in hypercholesterolemia and that autophagy is necessary for cardioprotection. However, it is unknown whether isolated hypercholesterolemia disturbs autophagy or the mammalian target of rapamycin (mTOR) pathways. Therefore, we investigated whether isolated hypercholesterolemia modulates cardiac autophagy-related pathways or programmed cell death mechanisms such as apoptosis and necroptosis in rat heart. Methods: Male Wistar rats were fed either normal chow (NORM; n = 9) or with 2% cholesterol and 0.25% cholic acid-enriched diet (CHOL; n = 9) for 12 weeks. CHOL rats exhibited a 41% increase in plasma total cholesterol level over that of NORM rats (4.09 mmol/L vs. 2.89 mmol/L) at the end of diet period. Animals were sacrificed, hearts were excised and briefly washed out. Left ventricles were snap-frozen for determination of markers of autophagy, mTOR pathway, apoptosis, and necroptosis by Western blot. Results: Isolated hypercholesterolemia was associated with a significant reduction in expression of cardiac autophagy markers such as LC3-II, Beclin-1, Rubicon and RAB7 as compared to controls. Phosphorylation of ribosomal S6, a surrogate marker for mTOR activity, was increased in CHOL samples. Cleaved caspase-3, a marker of apoptosis, increased in CHOL hearts, while no difference in the expression of necroptotic marker RIP1, RIP3 and MLKL was detected between treatments. Conclusions: This is the first comprehensive analysis of autophagy and programmed cell death pathways of apoptosis and necroptosis in hearts of hypercholesterolemic rats. Our data show that isolated hypercholesterolemia suppresses basal cardiac autophagy and that the decrease in autophagy may be a result of an activated mTOR pathway. Reduced autophagy was accompanied by increased apoptosis, while cardiac necroptosis was not modulated by isolated hypercholesterolemia. Decreased basal autophagy and elevated apoptosis may be responsible for the loss of cardioprotection reported in hypercholesterolemic animals.

AB - Background: We have previously shown that efficiency of ischemic conditioning is diminished in hypercholesterolemia and that autophagy is necessary for cardioprotection. However, it is unknown whether isolated hypercholesterolemia disturbs autophagy or the mammalian target of rapamycin (mTOR) pathways. Therefore, we investigated whether isolated hypercholesterolemia modulates cardiac autophagy-related pathways or programmed cell death mechanisms such as apoptosis and necroptosis in rat heart. Methods: Male Wistar rats were fed either normal chow (NORM; n = 9) or with 2% cholesterol and 0.25% cholic acid-enriched diet (CHOL; n = 9) for 12 weeks. CHOL rats exhibited a 41% increase in plasma total cholesterol level over that of NORM rats (4.09 mmol/L vs. 2.89 mmol/L) at the end of diet period. Animals were sacrificed, hearts were excised and briefly washed out. Left ventricles were snap-frozen for determination of markers of autophagy, mTOR pathway, apoptosis, and necroptosis by Western blot. Results: Isolated hypercholesterolemia was associated with a significant reduction in expression of cardiac autophagy markers such as LC3-II, Beclin-1, Rubicon and RAB7 as compared to controls. Phosphorylation of ribosomal S6, a surrogate marker for mTOR activity, was increased in CHOL samples. Cleaved caspase-3, a marker of apoptosis, increased in CHOL hearts, while no difference in the expression of necroptotic marker RIP1, RIP3 and MLKL was detected between treatments. Conclusions: This is the first comprehensive analysis of autophagy and programmed cell death pathways of apoptosis and necroptosis in hearts of hypercholesterolemic rats. Our data show that isolated hypercholesterolemia suppresses basal cardiac autophagy and that the decrease in autophagy may be a result of an activated mTOR pathway. Reduced autophagy was accompanied by increased apoptosis, while cardiac necroptosis was not modulated by isolated hypercholesterolemia. Decreased basal autophagy and elevated apoptosis may be responsible for the loss of cardioprotection reported in hypercholesterolemic animals.

KW - Apoptosis

KW - ATG8

KW - Autophagy

KW - Caspase

KW - Hypercholesterolemia

KW - Necroptosis

KW - Programmed necrosis

KW - Receptor-interacting serine/threonine-protein kinase

UR - http://www.scopus.com/inward/record.url?scp=85015917644&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85015917644&partnerID=8YFLogxK

U2 - 10.1186/s12944-017-0455-0

DO - 10.1186/s12944-017-0455-0

M3 - Article

VL - 16

JO - Lipids in Health and Disease

JF - Lipids in Health and Disease

SN - 1476-511X

IS - 1

M1 - 60

ER -