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.
- MeSH
- funkce levé komory srdeční účinky léků MeSH
- inhibitory proteinkinas * farmakologie MeSH
- kardiomyocyty * účinky léků patologie enzymologie MeSH
- krysa rodu rattus MeSH
- mikro RNA metabolismus genetika MeSH
- modely nemocí na zvířatech MeSH
- nekroptóza * účinky léků MeSH
- nekróza MeSH
- potkani Sprague-Dawley MeSH
- pyroptóza * účinky léků MeSH
- remodelace komor účinky léků MeSH
- serin-threoninkinasy interagující s receptory * antagonisté a inhibitory metabolismus MeSH
- srdeční selhání * patologie enzymologie patofyziologie farmakoterapie etiologie genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články 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.
Necroptosis has been recognized in heart failure (HF). In this study, we investigated detailed necroptotic signalling in infarcted and non-infarcted areas separately and its mechanistic link with main features of HF. Post-infarction HF in rats was induced by left coronary occlusion (60 minutes) followed by 42-day reperfusion. Heart function was assessed echocardiographically. Molecular signalling and proposed mechanisms (oxidative stress, collagen deposition and inflammation) were investigated in whole hearts and in subcellular fractions when appropriate. In post-infarction failing hearts, TNF and pSer229-RIP3 levels were comparably increased in both infarcted and non-infarcted areas. Its cytotoxic downstream molecule p-MLKL, indicating necroptosis execution, was detected in infarcted area. In non-infarcted area, despite increased pSer229-RIP3, p-MLKL was present in neither whole cells nor the cell membrane known to be associated with necroptosis execution. Likewise, increased membrane lipoperoxidation and NOX2 levels unlikely promoted pro-necroptotic environment in non-infarcted area. Collagen deposition and the inflammatory csp-1-IL-1β axis were active in both areas of failing hearts, while being more pronounced in infarcted tissue. Although apoptotic proteins were differently expressed in infarcted and non-infarcted tissue, apoptosis was found to play an insignificant role. p-MLKL-driven necroptosis and inflammation while inflammation only (without necroptotic cell death) seem to underlie fibrotic healing and progressive injury in infarcted and non-infarcted areas of failing hearts, respectively. Upregulation of pSer229-RIP3 in both HF areas suggests that this kinase, associated with both necroptosis and inflammation, is likely to play a dual role in HF progression.
- MeSH
- apoptóza fyziologie MeSH
- buněčná smrt fyziologie MeSH
- infarkt myokardu metabolismus MeSH
- kardiomyocyty metabolismus MeSH
- krysa rodu rattus MeSH
- nekroptóza fyziologie MeSH
- nekróza metabolismus MeSH
- oxidační stres fyziologie MeSH
- potkani Sprague-Dawley MeSH
- serin-threoninkinasy interagující s receptory metabolismus MeSH
- signální transdukce fyziologie MeSH
- srdeční selhání metabolismus MeSH
- upregulace fyziologie MeSH
- zánět metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In this study, we compared subjective fracture risks of Hungarian women with osteoporosis to FRAX®-based estimates. Patients with a previous fracture, parental hip fracture, low femoral T-score, higher age, and higher BMI were more likely to underestimate their risks. Patients also failed to associate risk factors with an increased risk of fractures. PURPOSE: The main objectives were to explore associations between self-perceived 10-year fracture risks of women with osteoporosis (OP) and their risks calculated by the FRAX® algorithm and to identify determinants of the underestimation of risk. METHODS: We carried out a cross-sectional study in 11 OP centers in Hungary and collected data on the risk factors considered by the FRAX® calculator. Patients estimated their subjective 10-year probability of any major osteoporotic and hip fracture numerically, in percentages and also on a visual analog scale (VAS). We compared subjective and FRAX® estimates and applied logistic regression to analyze the determinants of the underestimation of risk. Associations between risk factors and subjective risk were explored using linear probability models. RESULTS: Nine hundred seventy-two OP patients were included in the analysis. Major OP and hip fracture risk by FRAX® were on average 20.1 and 10.5%, while subjective estimates were significantly higher, 30.0 and 24.7%, respectively. Correlations between FRAX® and subjective measures were very weak (r = 0.12-0.16). Underestimation of major OP fracture risk was associated with having had a single previous fracture (OR = 2.0), parental hip fracture (OR = 3.4), femoral T-score ≤-2.5 (OR = 4.2), higher age, body mass index, and better general health state. We did not find significant associations between subjective risk estimates and most of the risk factors except for previous fractures. CONCLUSIONS: Hungarian OP patients fail to recognize most of the risk factors of fractures. Thus, education of patients about these risk factors would be beneficial especially for the elderly with a low femoral T-score and parental hip fracture history.
- MeSH
- absorpční fotometrie metody MeSH
- algoritmy MeSH
- diagnostické sebehodnocení * MeSH
- hodnocení rizik metody MeSH
- kostní denzita MeSH
- lidé středního věku MeSH
- lidé MeSH
- odhad potřeb MeSH
- osteoporotické fraktury * diagnóza epidemiologie psychologie MeSH
- průřezové studie MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
- Geografické názvy
- Maďarsko epidemiologie MeSH
