Cholesterol-enriched diet inhibits cardioprotection by ATP-sensitive K+ channel activators cromakalim and diazoxide

C. Csonka, Krisztina Kupai, Péter Bencsik, A. Görbe, János Pálóczi, A. Zvara, L. Puskás, T. Csont, P. Ferdinándy

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Abstract

It has been previously shown that hyperlipidemia interferes with cardioprotective mechanisms. Here, we investigated the interaction of hyperlipidemia with cardioprotection induced by pharmacological activators of ATP-sensitive K+ (KATP) channels. Hearts isolated from rats fed a 2% cholesterol-enriched diet or normal diet for 8 wk were subjected to 30 min of global ischemia and 120 min of reperfusion in the presence or absence of KATP modulators. In normal diet-fed rats, either the nonselective KATP activator cromakalim at 10-5 M or the selective mitochondrial (mito)KATP opener diazoxide at 3 × 10-5 M significantly decreased infarct size compared with vehicle-treated control rats. Their cardioprotective effect was abolished by coadministration of the nonselective KATP blocker glibenclamide or the selective mitoKATP blocker 5-hydroxydecanoate, respectively. However, in cholesterol-fed rats, the cardioprotective effect of cromakalim or diazoxide was not observed. Therefore, we further investigated how cholesterol-enriched diet influences cardiac KATP channels. Cardiac expression of a KATP subunit gene (Kir6.1) was significantly downregulated in cholesterol-fed rats; however, protein levels of Kir6.1 and Kir6.2 were not changed. The cholesterol diet significantly decreased cardiac ATP, increased lactate content, and enhanced myocardial oxidative stress, as shown by increased cardiac superoxide and dityrosine formation. This is the first demonstration that cardioprotection by KATP channel activators is impaired in cholesterol-enriched diet-induced hyperlipidemia. The background mechanism may include hyperlipidemia-induced attenuation of mitoKATP function by altered energy metabolism and increased oxidative stress in the heart.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume306
Issue number3
DOIs
Publication statusPublished - Feb 1 2014

Fingerprint

Cromakalim
Diazoxide
Adenosine Triphosphate
Cholesterol
Diet
Hyperlipidemias
KATP Channels
Oxidative Stress
Glyburide
Superoxides
Energy Metabolism
Reperfusion
Lactic Acid
Down-Regulation
Ischemia
Pharmacology
Genes

Keywords

  • ATP-sensitive potassium channel
  • Hyperlipidemia
  • Infarct size
  • Inward rectifier potassium channel
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

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title = "Cholesterol-enriched diet inhibits cardioprotection by ATP-sensitive K+ channel activators cromakalim and diazoxide",
abstract = "It has been previously shown that hyperlipidemia interferes with cardioprotective mechanisms. Here, we investigated the interaction of hyperlipidemia with cardioprotection induced by pharmacological activators of ATP-sensitive K+ (KATP) channels. Hearts isolated from rats fed a 2{\%} cholesterol-enriched diet or normal diet for 8 wk were subjected to 30 min of global ischemia and 120 min of reperfusion in the presence or absence of KATP modulators. In normal diet-fed rats, either the nonselective KATP activator cromakalim at 10-5 M or the selective mitochondrial (mito)KATP opener diazoxide at 3 × 10-5 M significantly decreased infarct size compared with vehicle-treated control rats. Their cardioprotective effect was abolished by coadministration of the nonselective KATP blocker glibenclamide or the selective mitoKATP blocker 5-hydroxydecanoate, respectively. However, in cholesterol-fed rats, the cardioprotective effect of cromakalim or diazoxide was not observed. Therefore, we further investigated how cholesterol-enriched diet influences cardiac KATP channels. Cardiac expression of a KATP subunit gene (Kir6.1) was significantly downregulated in cholesterol-fed rats; however, protein levels of Kir6.1 and Kir6.2 were not changed. The cholesterol diet significantly decreased cardiac ATP, increased lactate content, and enhanced myocardial oxidative stress, as shown by increased cardiac superoxide and dityrosine formation. This is the first demonstration that cardioprotection by KATP channel activators is impaired in cholesterol-enriched diet-induced hyperlipidemia. The background mechanism may include hyperlipidemia-induced attenuation of mitoKATP function by altered energy metabolism and increased oxidative stress in the heart.",
keywords = "ATP-sensitive potassium channel, Hyperlipidemia, Infarct size, Inward rectifier potassium channel, Oxidative stress",
author = "C. Csonka and Krisztina Kupai and P{\'e}ter Bencsik and A. G{\"o}rbe and J{\'a}nos P{\'a}l{\'o}czi and A. Zvara and L. Pusk{\'a}s and T. Csont and P. Ferdin{\'a}ndy",
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T1 - Cholesterol-enriched diet inhibits cardioprotection by ATP-sensitive K+ channel activators cromakalim and diazoxide

AU - Csonka, C.

AU - Kupai, Krisztina

AU - Bencsik, Péter

AU - Görbe, A.

AU - Pálóczi, János

AU - Zvara, A.

AU - Puskás, L.

AU - Csont, T.

AU - Ferdinándy, P.

PY - 2014/2/1

Y1 - 2014/2/1

N2 - It has been previously shown that hyperlipidemia interferes with cardioprotective mechanisms. Here, we investigated the interaction of hyperlipidemia with cardioprotection induced by pharmacological activators of ATP-sensitive K+ (KATP) channels. Hearts isolated from rats fed a 2% cholesterol-enriched diet or normal diet for 8 wk were subjected to 30 min of global ischemia and 120 min of reperfusion in the presence or absence of KATP modulators. In normal diet-fed rats, either the nonselective KATP activator cromakalim at 10-5 M or the selective mitochondrial (mito)KATP opener diazoxide at 3 × 10-5 M significantly decreased infarct size compared with vehicle-treated control rats. Their cardioprotective effect was abolished by coadministration of the nonselective KATP blocker glibenclamide or the selective mitoKATP blocker 5-hydroxydecanoate, respectively. However, in cholesterol-fed rats, the cardioprotective effect of cromakalim or diazoxide was not observed. Therefore, we further investigated how cholesterol-enriched diet influences cardiac KATP channels. Cardiac expression of a KATP subunit gene (Kir6.1) was significantly downregulated in cholesterol-fed rats; however, protein levels of Kir6.1 and Kir6.2 were not changed. The cholesterol diet significantly decreased cardiac ATP, increased lactate content, and enhanced myocardial oxidative stress, as shown by increased cardiac superoxide and dityrosine formation. This is the first demonstration that cardioprotection by KATP channel activators is impaired in cholesterol-enriched diet-induced hyperlipidemia. The background mechanism may include hyperlipidemia-induced attenuation of mitoKATP function by altered energy metabolism and increased oxidative stress in the heart.

AB - It has been previously shown that hyperlipidemia interferes with cardioprotective mechanisms. Here, we investigated the interaction of hyperlipidemia with cardioprotection induced by pharmacological activators of ATP-sensitive K+ (KATP) channels. Hearts isolated from rats fed a 2% cholesterol-enriched diet or normal diet for 8 wk were subjected to 30 min of global ischemia and 120 min of reperfusion in the presence or absence of KATP modulators. In normal diet-fed rats, either the nonselective KATP activator cromakalim at 10-5 M or the selective mitochondrial (mito)KATP opener diazoxide at 3 × 10-5 M significantly decreased infarct size compared with vehicle-treated control rats. Their cardioprotective effect was abolished by coadministration of the nonselective KATP blocker glibenclamide or the selective mitoKATP blocker 5-hydroxydecanoate, respectively. However, in cholesterol-fed rats, the cardioprotective effect of cromakalim or diazoxide was not observed. Therefore, we further investigated how cholesterol-enriched diet influences cardiac KATP channels. Cardiac expression of a KATP subunit gene (Kir6.1) was significantly downregulated in cholesterol-fed rats; however, protein levels of Kir6.1 and Kir6.2 were not changed. The cholesterol diet significantly decreased cardiac ATP, increased lactate content, and enhanced myocardial oxidative stress, as shown by increased cardiac superoxide and dityrosine formation. This is the first demonstration that cardioprotection by KATP channel activators is impaired in cholesterol-enriched diet-induced hyperlipidemia. The background mechanism may include hyperlipidemia-induced attenuation of mitoKATP function by altered energy metabolism and increased oxidative stress in the heart.

KW - ATP-sensitive potassium channel

KW - Hyperlipidemia

KW - Infarct size

KW - Inward rectifier potassium channel

KW - Oxidative stress

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