In 2023, six decades have elapsed since the first experimental work on the heart muscle was published, in which a member of the Institute of Physiology of the Czech Academy of Sciences participated as an author; Professor Otakar Poupa was the founder and protagonist of this research domain. Sixty years - more than half of the century - is certainly significant enough anniversary that is worth looking back and reflecting on what was achieved during sometimes very complicated periods of life. It represents the history of an entire generation of experimental cardiologists; it is possible to learn from its successes and mistakes. The objective of this review is to succinctly illuminate the scientific trajectory of an experimental cardiological department over a 60-year span, from its inaugural publication to the present. The old truth - historia magistra vitae - is still valid. Keywords: Heart, Adaptation, Development, Hypoxia, Protection.

• MeSH
• Academies and Institutes * history   MeSH
• Biomedical Research * history   trends   MeSH
• History, 20th Century MeSH
• History, 21st Century MeSH
• Physiology history   MeSH
• Cardiology history   trends   MeSH
• Humans MeSH
• Heart physiology   MeSH
• Animals MeSH
• Check Tag
• History, 20th Century MeSH
• History, 21st Century MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Review MeSH
• Geographicals
• Czech Republic MeSH

The purpose of this review is to analyze the involvement of protein kinases in the cardioprotective mechanism induced by chronic hypoxia. It has been reported that chronic intermittent hypoxia contributes to increased expression of the following kinases in the myocardium: PKCdelta, PKCalpha, p-PKCepsilon, p-PKCalpha, AMPK, p-AMPK, CaMKII, p-ERK1/2, p-Akt, PI3-kinase, p-p38, HK-1, and HK-2; whereas, chronic normobaric hypoxia promotes increased expression of the following kinases in the myocardium: PKCepsilon, PKCbetaII, PKCeta, CaMKII, p-ERK1/2, p-Akt, p-p38, HK-1, and HK-2. However, CNH does not promote enhanced expression of the AMPK and JNK kinases. Adaptation to hypoxia enhances HK-2 association with mitochondria and causes translocation of PKCdelta, PKCbetaII, and PKCeta to the mitochondria. It has been shown that PKCdelta, PKCepsilon, ERK1/2, and MEK1/2 are involved in the cardioprotective effect of chronic hypoxia. The role of other kinases in the cardioprotective effect of adaptation to hypoxia requires further research.

• MeSH
• Chronic Disease MeSH
• Hypoxia enzymology   MeSH
• Cardiotonic Agents pharmacology   MeSH
• Humans MeSH
• Heart Diseases enzymology   etiology   prevention & control   MeSH
• Protein Kinases metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Cardiotonic Agents MeSH
• Protein Kinases MeSH

Adaptation to chronic hypoxia renders the heart more tolerant to ischemia/reperfusion injury. To evaluate changes in gene expression after adaptation to chronic hypoxia by RT-qPCR, it is essential to select suitable reference genes. In a chronically hypoxic rat model, no specific reference genes have been identified in the myocardium. This study aimed to select the best reference genes in the left (LV) and right (RV) ventricles of chronically hypoxic and normoxic rats. Sprague-Dawley rats were adapted to continuous normobaric hypoxia (CNH; 12% O2 or 10% O2) for 3 weeks. The expression levels of candidate genes were assessed by RT-qPCR. The stability of genes was evaluated by NormFinder, geNorm and BestKeeper algorithms. The best five reference genes in the LV were Top1, Nupl2, Rplp1, Ywhaz, Hprt1 for the milder CNH and Top1, Ywhaz, Sdha, Nupl2, Tomm22 for the stronger CNH. In the RV, the top five genes were Hprt1, Nupl2, Gapdh, Top1, Rplp1 for the milder CNH and Tomm22, Gapdh, Hprt1, Nupl2, Top1 for the stronger CNH. This study provides validation of reference genes in LV and RV of CNH rats and shows that suitable reference genes differ in the two ventricles and depend on experimental protocol.

• Keywords
• Chronic hypoxia, Heart, Left ventricle, RT-qPCR, Rat, Reference genes,
• MeSH
• Chronic Disease MeSH
• Hypoxia genetics   MeSH
• Myocardium metabolism   pathology   MeSH
• Rats, Sprague-Dawley MeSH
• Reference Standards MeSH
• Gene Expression Regulation * MeSH
• Heart Ventricles metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Chronic hypoxia protects the heart against injury caused by acute oxygen deprivation, but its salutary mechanism is poorly understood. The aim was to find out whether cardiomyocytes isolated from chronically hypoxic hearts retain the improved resistance to injury and whether the mitochondrial large-conductance Ca2+-activated K+ (BKCa) channels contribute to the protective effect. Adult male rats were adapted to continuous normobaric hypoxia (inspired O2 fraction 0.10) for 3 wk or kept at room air (normoxic controls). Myocytes, isolated separately from the left ventricle (LVM), septum (SEPM), and right ventricle, were exposed to 25-min metabolic inhibition with sodium cyanide, followed by 30-min reenergization (MI/R). Some LVM were treated with either 30 μM NS-1619 (BKCa opener), or 2 μM paxilline (BKCa blocker), starting 25 min before metabolic inhibition. Cell injury was detected by Trypan blue exclusion and lactate dehydrogenase (LDH) release. Chronic hypoxia doubled the number of rod-shaped LVM and SEPM surviving the MI/R insult and reduced LDH release. While NS-1619 protected cells from normoxic rats, it had no additive salutary effect in the hypoxic group. Paxilline attenuated the improved resistance of cells from hypoxic animals without affecting normoxic controls; it also abolished the protective effect of NS-1619 on LDH release in the normoxic group. While chronic hypoxia did not affect protein abundance of the BKCa channel regulatory β1-subunit, it markedly decreased its glycosylation level. It is concluded that ventricular myocytes isolated from chronically hypoxic rats retain the improved resistance against injury caused by MI/R. Activation of the mitochondrial BKCa channel likely contributes to this protective effect.

• MeSH
• Benzimidazoles pharmacology   MeSH
• Potassium Channel Blockers pharmacology   MeSH
• Chronic Disease MeSH
• Glycosylation MeSH
• Hypoxia physiopathology   MeSH
• Indoles pharmacology   MeSH
• Ischemic Preconditioning, Myocardial MeSH
• Myocytes, Cardiac drug effects   physiology   MeSH
• Rats MeSH
• Cells, Cultured MeSH
• L-Lactate Dehydrogenase metabolism   MeSH
• Rats, Wistar MeSH
• Myocardial Reperfusion Injury physiopathology   prevention & control   MeSH
• Cell Separation MeSH
• Mitochondria, Heart drug effects   physiology   MeSH
• Large-Conductance Calcium-Activated Potassium Channel beta Subunits physiology   MeSH
• Large-Conductance Calcium-Activated Potassium Channels antagonists & inhibitors   physiology   MeSH
• Cell Survival MeSH
• Blotting, Western MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Benzimidazoles MeSH
• Potassium Channel Blockers MeSH
• Indoles MeSH
• L-Lactate Dehydrogenase MeSH
• NS 1619 MeSH Browser
• paxilline MeSH Browser
• Large-Conductance Calcium-Activated Potassium Channel beta Subunits MeSH
• Large-Conductance Calcium-Activated Potassium Channels MeSH

The adaptation to chronic hypoxia confers long-lasting cardiac protection against acute ischemia-reperfusion injury. Protein kinase C (PKC) appears to play a role in the cardioprotective mechanism but the involvement of individual PKC isoforms remains unclear. The aim of this study was to examine the effects of chronic intermittent hypoxia (CIH; 7,000 m, 8 h/day) and acute administration of PKC-δ inhibitor (rottlerin, 0.3 mg/kg) on the expression and subcellular distribution of PKC-δ and PKC-ε in the left ventricular myocardium of adult male Wistar rats by Western blot and quantitative immunofluorescence microscopy. CIH decreased the total level of PKC-ε in homogenate without affecting the level of phosphorylated PKC-ε (Ser729). In contrast, CIH up-regulated the total level of PKC-δ as well as the level of phosphorylated PKC-δ (Ser643) in homogenate. Rottlerin partially reversed the hypoxia-induced increase in PKC-δ in the mitochondrial fraction. Immunofluorescent staining of ventricular cryo-sections revealed increased co-localization of PKC-δ with mitochondrial and sarcolemmal membranes in CIH hearts that was suppressed by rottlerin. The formation of nitrotyrosine as a marker of oxidative stress was enhanced in CIH myocardium, particularly in mitochondria. The expression of total oxidative phosphorylation complexes was slightly decreased by CIH mainly due to complex II decline. In conclusion, up-regulated PKC-δ in CIH hearts is mainly localized to mitochondrial and sarcolemmal membranes. The inhibitory effects of rottlerin on PKC-δ subcellular redistribution and cardioprotection (as shown previously) support the view that this isoform plays a role in the mechanism of CIH-induced ischemic tolerance.

• MeSH
• Chronic Disease MeSH
• Phosphorylation MeSH
• Hypoxia enzymology   MeSH
• Protein Kinase Inhibitors pharmacology   MeSH
• Rats MeSH
• Mitochondria metabolism   MeSH
• Myocardium metabolism   pathology   MeSH
• Protective Agents MeSH
• Rats, Wistar MeSH
• Protein Kinase C-delta genetics   metabolism   physiology   MeSH
• Sarcolemma metabolism   MeSH
• Tissue Distribution MeSH
• Up-Regulation * MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Protein Kinase Inhibitors MeSH
• Protective Agents MeSH
• Protein Kinase C-delta MeSH

• Publication type
• Journal Article MeSH