Since cell dying in heart failure (HF) may vary based on the aetiology, we examined the main forms of regulated necrosis, such as necroptosis and pyroptosis, in the hearts damaged due to myocardial infarction (MI) or pressure overload. We also investigated the effects of a drug inhibiting RIP3, a proposed convergent point for both these necrosis-like cell death modes. In rat hearts, left ventricular function, remodelling, pro-cell death, and pro-inflammatory events were investigated, and the pharmacodynamic action of RIP3 inhibitor (GSK'872) was assessed. Regardless of the HF aetiology, the heart cells were dying due to necroptosis, albeit the upstream signals may be different. Pyroptosis was observed only in post-MI HF. The dysregulated miRNAs in post-MI hearts were accompanied by higher levels of a predicted target, HMGB1, its receptors (TLRs), as well as the exacerbation of inflammation likely originating from macrophages. The RIP3 inhibitor suppressed necroptosis, unlike pyroptosis, normalised the dysregulated miRNAs and tended to decrease collagen content and affect macrophage infiltration without affecting cardiac function or structure. The drug also mitigated the local heart inflammation and normalised the higher circulating HMGB1 in rats with post-MI HF. Elevated serum levels of HMGB1 were also detected in HF patients and positively correlated with C-reactive protein, highlighting pro-inflammatory axis. In conclusion, in MI-, but not pressure overload-induced HF, both necroptosis and pyroptosis operate and might underlie HF pathogenesis. The RIP3-targeting pharmacological intervention might protect the heart by preventing pro-death and pro-inflammatory mechanisms, however, additional strategies targeting multiple pro-death pathways may exhibit greater cardioprotection.

• Keywords
• Heart failure, High mobility group box 1, Inflammation, Necroptosis, Pyroptosis, Receptor-interacting protein kinase 3,
• MeSH
• Ventricular Function, Left drug effects   MeSH
• Protein Kinase Inhibitors * pharmacology   MeSH
• Myocytes, Cardiac * drug effects   pathology   enzymology   MeSH
• Rats MeSH
• MicroRNAs metabolism   genetics   MeSH
• Disease Models, Animal MeSH
• Necroptosis * drug effects   MeSH
• Necrosis MeSH
• Rats, Sprague-Dawley MeSH
• Pyroptosis * drug effects   MeSH
• Ventricular Remodeling drug effects   MeSH
• Receptor-Interacting Protein Serine-Threonine Kinases * antagonists & inhibitors   metabolism   MeSH
• Heart Failure * pathology   enzymology   physiopathology   drug therapy   etiology   genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Protein Kinase Inhibitors * MeSH
• MicroRNAs MeSH
• Ripk3 protein, rat MeSH Browser
• Receptor-Interacting Protein Serine-Threonine Kinases * MeSH

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

Diabetes mellitus is known to produce various cell-damaging events and thereby underlie heart dysfunction and remodeling. However, very little is known about its inflammation-associated pathomechanisms due to necrosis-like cell death. For this purpose, we aimed to investigate signaling pathways of necroptosis and pyroptosis, known to produce plasma membrane rupture with the resultant promotion of inflammation. One-year old Zucker diabetic fatty (ZDF) rats did not exhibit significant heart dysfunction as revealed by echocardiographic measurement. On the other hand, there was a decrease in heart rate due to diabetes. Immunoblotting analysis showed that the left ventricles of ZDF rats overexpress neither the main necroptotic proteins including receptor-interacting protein kinase 3 (RIP3) and mixed lineage domain kinase-like pseudokinase (MLKL), nor the pyroptotic regulators including NLR family pyrin domain containing 3 protein (NLRP3), caspase-1, interleukin-1 beta (IL-1beta and the N-terminal gasdermin D (GSDMD-N). On the other hand, the increased activation of the RIP3 kinase due to phosphorylation was found in such hearts. In summary, we showed for the first time that the activation of cardiac RIP3 is upregulated due to disturbances in glucose metabolism which, however, did not proceed to necrosis-like cell death. These data can indicate that the activated RIP3 might also underlie other pleiotropic, non-necroptotic signaling pathways under basal conditions.

• MeSH
• Apoptosis MeSH
• Diabetes Mellitus, Type 2 * MeSH
• Rats MeSH
• Necrosis MeSH
• Rats, Zucker MeSH
• Protein Kinases metabolism   MeSH
• Pyroptosis * MeSH
• Signal Transduction MeSH
• Inflammation MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Protein Kinases MeSH

The aim of the present study was to explore whether hydrogen sulfide (H2S) protects against ischemic heart failure (HF) by inhibiting the necroptosis pathway. Mice were randomized into Sham, myocardial infarction (MI), MI + propargylglycine (PAG) and MI + sodium hydrosulfide (NaHS) group, respectively. The MI model was induced by ligating the left anterior descending coronary artery. PAG was intraperitoneally administered at a dose of 50 mg/kg/day for 4 weeks, and NaHS at a dose of 4 mg/kg/day for the same period. At 4 weeks after MI, the following were observed: A significant decrease in the cardiac function, as evidenced by a decline in ejection fraction (EF) and fractional shortening (FS); an increase in plasma myocardial injury markers, such as creatine kinase-MB (CK-MB) and cardiac troponin I (cTNI); an increase in myocardial collagen content in the heart tissues; and a decrease of H2S level in plasma and heart tissues. Furthermore, the expression levels of necroptosis-related markers such as receptor interacting protein kinase 1 (RIP1), RIP3 and mixed lineage kinase domain-like protein (MLKL) were upregulated after MI. NaHS treatment increased H2S levels in plasma and heart tissues, preserving the cardiac function by increasing EF and FS, decreasing plasma CK-MB and cTNI and reducing collagen content. Additionally, NaHS treatment significantly downregulated the RIP1/RIP3/MLKL pathway. While, PAG treatment aggravated cardiac function by activated the RIP1/RIP3/MLKL pathway. Overall, the present study concluded that H2S protected against ischemic HF by inhibiting RIP1/RIP3/MLKL-mediated necroptosis which could be a potential target treatment for ischemic HF.

• MeSH
• Myocardial Infarction * prevention & control   MeSH
• Mice MeSH
• Necroptosis MeSH
• Protein Kinases metabolism   MeSH
• Heart Failure * drug therapy   prevention & control   MeSH
• Hydrogen Sulfide * MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• MLKL protein, mouse MeSH Browser
• Protein Kinases MeSH
• sodium bisulfide MeSH Browser
• Hydrogen Sulfide * MeSH

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