Most cited article - PubMed ID 30979784
Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats
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
Cardiovascular and heart diseases are leading causes of morbidity and mortality. Coronary artery endothelial and vascular dysfunction, inflammation, and mitochondrial dysfunction contribute to progression of heart diseases such as arrhythmias, congestive heart failure, and heart attacks. Classes of fatty acid epoxylipids and their enzymatic regulation by soluble epoxide hydrolase (sEH) have been implicated in coronary artery dysfunction, inflammation, and mitochondrial dysfunction in heart diseases. Likewise, genetic and pharmacological manipulations of epoxylipids have been demonstrated to have therapeutic benefits for heart diseases. Increasing epoxylipids reduce cardiac hypertrophy and fibrosis and improve cardiac function. Beneficial actions for epoxylipids have been demonstrated in cardiac ischemia reperfusion injury, electrical conductance abnormalities and arrhythmias, and ventricular tachycardia. This review discusses past and recent findings on the contribution of epoxylipids in heart diseases and the potential for their manipulation to treat heart attacks, arrhythmias, ventricular tachycardia, and heart failure.
- Keywords
- Coronary artery, Cytochrome P450, Eicosanoids, Heart failure, Hypertension, Inflammation, Mitochondrial function, Myocardial infarction, Soluble epoxide hydrolase,
- MeSH
- Epoxide Hydrolases antagonists & inhibitors metabolism MeSH
- Epoxy Compounds chemistry metabolism MeSH
- Myocardial Infarction drug therapy enzymology metabolism MeSH
- Enzyme Inhibitors therapeutic use MeSH
- Tachycardia, Ventricular drug therapy enzymology metabolism MeSH
- Humans MeSH
- Fatty Acids metabolism MeSH
- Heart Diseases drug therapy enzymology metabolism MeSH
- Solubility MeSH
- Arrhythmias, Cardiac drug therapy enzymology metabolism MeSH
- Heart Failure drug therapy enzymology metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Research Support, N.I.H., Extramural MeSH
- Names of Substances
- Epoxide Hydrolases MeSH
- Epoxy Compounds MeSH
- Enzyme Inhibitors MeSH
- Fatty Acids MeSH
This study evaluates the effects of chronic treatment with EET-A, an orally active epoxyeicosatrienoic acid (EETs) analog, on the course of aorto-caval fistula (ACF)-induced heart failure (HF) in Ren-2 transgenic rats (TGR), a model characterized by hypertension and augmented activity of the renin-angiotensin system (RAS). The results were compared with standard pharmacological blockade of the RAS using angiotensin-converting enzyme inhibitor (ACEi). The rationale for employing EET-A as a new treatment approach is based on our findings that apart from increased RAS activity, untreated ACF TGR also shows kidney and left ventricle (LV) tissue deficiency of EETs. Untreated ACF TGR began to die 17 days after creating ACF and were all dead by day 84. The treatment with EET-A alone or ACEi alone improved the survival rate: in 156 days after ACF creation, it was 45.5% and 59.4%, respectively. The combined treatment with EET-A and ACEi appeared to improve the final survival to 71%; however, the difference from either single treatment regimen did not reach significance. Nevertheless, our findings support the notion that targeting the cytochrome P-450-dependent epoxygenase pathway of arachidonic acid metabolism should be considered for the treatment of HF.
While necroptosis has been shown to contribute to the pathogenesis of post-infarction heart failure (HF), the role of autophagy remains unclear. Likewise, linkage between these two cell death modalities has not been sufficiently investigated. HF was induced by 60-min left coronary occlusion in adult Wistar rats and heart function was assessed 6 weeks later followed by immunoblotting analysis of necroptotic and autophagic proteins in both the left (LV) and right ventricle (RV). HF had no effect on RIP1 and RIP3 expression. PhosphoSer229-RIP3, acting as a pro-necroptotic signal, was increased in LV while deceased in RV of failing hearts. Total MLKL was elevated in RV only. Decrease in pSer555-ULK1, increase in pSer473-Akt and no significant elevation in beclin-1 and LC3-II/I ratio indicated rather a lowered rate of autophagy in LV. No beclin-1 upregulation and decreased LC3 processing also suggested the inhibition of both autophagosome formation and maturation in RV of failing hearts. In contrast, p89 PARP1 fragment, a marker of executed apoptosis, was increased in RV only. This is the first study showing a different signaling in ventricles of the late phase of post-infarction HF, highlighting necroptosis itself rather than its linkage with autophagy in LV, and apoptosis in RV.
- Keywords
- autophagy, cell death, heart failure, necroptosis,
- MeSH
- Apoptosis * physiology MeSH
- Autophagy physiology MeSH
- Myocardial Infarction complications pathology MeSH
- Necroptosis physiology MeSH
- Rats, Sprague-Dawley MeSH
- Rats, Wistar MeSH
- Protein Serine-Threonine Kinases metabolism MeSH
- Receptor-Interacting Protein Serine-Threonine Kinases metabolism MeSH
- Signal Transduction MeSH
- Heart Ventricles pathology MeSH
- Heart Failure etiology metabolism pathology MeSH
- Organ Size MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Protein Serine-Threonine Kinases MeSH
- RIPK1 protein, rat MeSH Browser
- Ripk3 protein, rat MeSH Browser
- Receptor-Interacting Protein Serine-Threonine Kinases MeSH
