scholarly journals Catecholamine Surges Cause Cardiomyocyte Necroptosis via a RIPK1–RIPK3-Dependent Pathway in Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Penglong Wu ◽  
Mingqi Cai ◽  
Jinbao Liu ◽  
Xuejun Wang

Background: Catecholamine surges and resultant excessive β-adrenergic stimulation occur in a broad spectrum of diseases. Excessive β-adrenergic stimulation causes cardiomyocyte necrosis, but the underlying mechanism remains obscure. Necroptosis, a major form of regulated necrosis mediated by RIPK3-centered pathways, is implicated in heart failure; however, it remains unknown whether excessive β-adrenergic stimulation-induced cardiac injury involves necroptosis. Hence, we conducted the present study to address these critical gaps.Methods and Results: Two consecutive daily injections of isoproterenol (ISO; 85 mg/kg, s.c.) or saline were administered to adult mixed-sex mice. At 24 h after the second ISO injection, cardiac area with Evans blue dye (EBD) uptake and myocardial protein levels of CD45, RIPK1, Ser166-phosphorylated RIPK1, RIPK3, and Ser345-phosphorylated MLKL (p-MLKL) were significantly greater, while Ser321-phosphorylated RIPK1 was significantly lower, in the ISO-treated than in saline-treated wild-type (WT) mice. The ISO-induced increase of EBD uptake was markedly less in RIPK3−/− mice compared with WT mice (p = 0.016). Pretreatment with the RIPK1-selective inhibitor necrostatin-1 diminished ISO-induced increases in RIPK3 and p-MLKL in WT mice and significantly attenuated ISO-induced increases of EBD uptake in WT but not RIPK3−/− mice.Conclusions: A large proportion of cardiomyocyte necrosis induced by excessive β-adrenergic stimulation belongs to necroptosis and is mediated by a RIPK1–RIPK3-dependent pathway, identifying RIPK1 and RIPK3 as potential therapeutic targets for catecholamine surges.

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Felix A Trogisch ◽  
Franziska Koser ◽  
Andreas Jungmann ◽  
Oliver J Müller ◽  
Markus Hecker ◽  
...  

2015 ◽  
Vol 309 (5) ◽  
pp. L497-L505 ◽  
Author(s):  
Bumsoo Ahn ◽  
Adam W. Beharry ◽  
Gregory S. Frye ◽  
Andrew R. Judge ◽  
Leonardo F. Ferreira

Patients with chronic heart failure (CHF) have dyspnea and exercise intolerance, which are caused in part by diaphragm abnormalities. Oxidants impair diaphragm contractile function, and CHF increases diaphragm oxidants. However, the specific source of oxidants and its relevance to diaphragm abnormalities in CHF is unclear. The p47phox-dependent Nox2 isoform of NAD(P)H oxidase is a putative source of diaphragm oxidants. Thus, we conducted our study with the goal of determining the effects of CHF on the diaphragm levels of Nox2 complex subunits and test the hypothesis that p47phox knockout prevents diaphragm contractile dysfunction elicited by CHF. CHF caused a two- to sixfold increase ( P < 0.05) in diaphragm mRNA and protein levels of several Nox2 subunits, with p47phox being upregulated and hyperphosphorylated. CHF increased diaphragm extracellular oxidant emission in wild-type but not p47phox knockout mice. Diaphragm isometric force, shortening velocity, and peak power were decreased by 20–50% in CHF wild-type mice ( P < 0.05), whereas p47phox knockout mice were protected from impairments in diaphragm contractile function elicited by CHF. Our experiments show that p47phox is upregulated and involved in the increased oxidants and contractile dysfunction in CHF diaphragm. These findings suggest that a p47phox-dependent NAD(P)H oxidase mediates the increase in diaphragm oxidants and contractile dysfunction in CHF.


2004 ◽  
Vol 286 (3) ◽  
pp. H1146-H1153 ◽  
Author(s):  
Jo El J. Schultz ◽  
Betty J. Glascock ◽  
Sandra A. Witt ◽  
Michelle L. Nieman ◽  
Kalpana J. Nattamai ◽  
...  

We recently developed a mouse model with a single functional allele of Serca2 ( Serca2+/–) that shows impaired cardiac contractility and relaxation without overt heart disease. The goal of this study was to test the hypothesis that chronic reduction in sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 levels in combination with an increased hemodynamic load will result in an accelerated pathway to heart failure. Age-matched wild-type and Serca2+/– mice were subjected to 10 wk of pressure overload via transverse aortic coarctation surgery. Cardiac hypertrophy and heart failure were assessed by echocardiography, gravimetry/histology, hemodynamics, and Western blotting analyses. Our results showed that ∼64% of coarcted Serca2+/– mice were in heart failure compared with 0% of coarcted wild-type mice ( P < 0.05). Overall, morbidity and mortality were greatly increased in Serca2+/– mice under pressure overload. Echocardiography assessment revealed a significant increase in left ventricular (LV) mass, and LV hypertrophy in coarcted Serca2+/– mice converted from a concentric to an eccentric pattern, similar to that seen in human heart failure. Coarcted Serca2+/– mice had decreased contractile/systolic and relaxation/diastolic performance and/or function compared with coarcted wild-type mice ( P < 0.05), despite a similar duration and degree of pressure overload. SERCA2a protein levels were significantly reduced (>50%) in coarcted Serca2+/– mice compared with noncoarcted and coarcted wild-type mice. Our findings suggest that reduction in SERCA2 levels in combination with an increased hemodynamic load results in an accelerated pathway to heart failure.


2015 ◽  
Vol 5 (1) ◽  
Author(s):  
J. Patrick Gonzalez ◽  
Jayalakshmi Ramachandran ◽  
Lai-Hua Xie ◽  
Jorge E. Contreras ◽  
Diego Fraidenraich

Abstract Duchenne muscular dystrophy (DMD) is caused by an X-linked mutation that leads to the absence of dystrophin, resulting in life-threatening arrhythmogenesis and associated heart failure. We targeted the gap junction protein connexin43 (Cx43) responsible for maintaining cardiac conduction. In mild mdx and severe mdx:utr mouse models of DMD and human DMD tissues, Cx43 was found to be pathologically mislocalized to lateral sides of cardiomyocytes. In addition, overall Cx43 protein levels were markedly increased in mouse and human DMD heart tissues examined. Electrocardiography on isoproterenol challenged mice showed that both models developed arrhythmias and died within 24 hours, while wild-type mice were free of pathology. Administering peptide mimetics to inhibit lateralized Cx43 function prior to challenge protected mdx mice from arrhythmogenesis and death, while mdx:utr mice displayed markedly improved ECG scores. These findings suggest that Cx43 lateralization contributes significantly to DMD arrhythmogenesis and that selective inhibition may provide substantial benefit.


2013 ◽  
Vol 114 (8) ◽  
pp. 979-987 ◽  
Author(s):  
Soochan Bae ◽  
Sylvia S. Singh ◽  
Hyeon Yu ◽  
Ji Yoo Lee ◽  
Byung Ryul Cho ◽  
...  

Accumulating evidence suggests that vitamin D deficiency plays a crucial role in heart failure. However, whether vitamin D signaling itself plays an important role in cardioprotection is poorly understood. In this study, we examined the mechanism of modulating vitamin D signaling on progression to heart failure after myocardial infarction (MI) in mice. Vitamin D signaling was activated by administration of paricalcitol (PC), an activated vitamin D analog. Wild-type (WT) mice underwent sham or MI surgery and then were treated with either vehicle or PC. Compared with vehicle group, PC attenuated development of heart failure after MI associated with decreases in biomarkers, apoptosis, inflammation, and fibrosis. There was also improvement of cardiac function with PC treatment after MI. Furthermore, vitamin D receptor (VDR) mRNA and protein levels were restored by PC treatment. Next, to explore whether defective vitamin D signaling exhibited deleterious responses after MI, WT and VDR knockout (KO) mice underwent sham or MI surgery and were analyzed 4 wk after MI. VDR KO mice displayed a significant decline in survival rate and cardiac function compared with WT mice after MI. VDR KO mice also demonstrated a significant increase in heart failure biomarkers, apoptosis, inflammation, and fibrosis. Vitamin D signaling promotes cardioprotection after MI through anti-inflammatory, antifibrotic and antiapoptotic mechanisms.


2020 ◽  
Author(s):  
Jie Ni ◽  
Yihai Liu ◽  
Kun Wang ◽  
Wenfeng Zhang ◽  
Zhonglin Han ◽  
...  

Abstract Purpose:Human trophoblast stem cells (TSC)have been confirmed to play a cardioprotective role in heart failure. However, whether trophoblast stem cell derived exosomes (TSC-Exos) can protect cardiomyocytes from doxorubicin (Dox) induced injury remains unclear. Methods:In the present study, TSC-Exos were isolated from the supernatant of Human Trophoblasts using the ultracentrifugation method and characterized by transmission electron microscope and western blotting.In vitro, primary cardiomyocytes subjected to Dox were treated with TSC-Exos, miR-200b mimic or miR-200b inhibitor. Cell apoptosis was observed by flow cytometry and immunoblotting. In vivo, mice were intraperitoneally injected into Dox to establish a heart failure model. Then they received a tail injection of either PBS, adeno-associated virus (AAV)-vector, AAV-miR-200b-inhibitor or TSC-Exosfor different groups. Then cardiac function, cardiac fibrosis and cardiomyocyte apoptosis among groups were evaluated and downstream molecular mechanism was explored. Results: TSC-Exos and miR-200b inhibitor both decreased primary cardiomyocytes apoptosis. Similarly, mice receivingTSC-Exos andAAV-miR-200b-inhibitor have improved cardiac function, accompanied by reduced apoptosis and inflammation. Bioinformatic prediction and luciferase reporter results confirmed that Zeb1 was a downstream target of miR-200b, which had an antiapoptotic effect. Conclusion:TSC-ExosattenuatedDoxorubicin induced cardiac injury by playing an antiapoptosis and antiinflammation role. The underlying mechanism could be increased expression of Zeb1 by inhibiting miR-200b expression, due to the TSC-Exos treatment. This study sheds newlight on the application of MSC-Exo as a potential therapeutic tool for heart failure.


2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Christiane Vettel ◽  
Hind Mehel ◽  
Julius Emons ◽  
Katrin Wittkoepper ◽  
Danilo Seppelt ◽  
...  

Augmented cGMP- and diminished cAMP-signaling within cardiomyocytes is characteristic for failing hearts. Cyclic nucleotide phosphodiesterases (PDEs) comprise a family of cyclic-nucleotide hydrolyzing enzymes, controlling cAMP and cGMP levels. Among them the PDE-2A isoform has the unique property to be stimulated by cGMP but primarily hydrolyzing cAMP. This appears to mediate a negative cross-talk between both signaling pathways. However, a potential role for PDE-2A in the failing heart has not been addressed yet. Here we show that PDE-2A protein levels were ∼2-fold higher in failing human hearts as well as in a large animal heart failure model from dog hearts subjected to rapid-pacing (n≥6, p<0.05). Intriguingly, PDE-2A protein levels were normal in hypertrophied hearts from patients with preserved cardiac function who underwent aortic valve replacement. Chronic beta-adrenergic stimulation by catecholamine infusions enhanced cAMP hydrolyzing activity of PDE-2A by four-fold (n≥6, p<0.05) in rat hearts in vivo and in isolated cardiomyocytes (measured by radioimmunoassay and FRET-based sensors, respectively) and correlated with blunted beta-adrenergic responsiveness. Consistent with this observation, overexpressed PDE-2A, which localized to the sarcomeric Z-line, blunted the rise in cAMP by 70% (n≥6, p<0.05) and abolished the positive inotropic effect after acute beta-adrenergic stimulation by 70% (n≥6, p<0.05) in isolated cardiomyocytes. Notably, those cardiomyocytes also showed marked protection from norepinephrine-induced hypertrophic responses, e. g. 40% less increase in cell surface area (n≥10, p<0.05). In summary, PDE-2A is markedly upregulated in human and experimental failing hearts. This may constitute an important defense mechanism during cardiac stress, by antagonizing the cAMP-mediated toxic effects. Thus, activating myocardial PDE-2A may represent a new intracellular anti-adrenergic therapeutic strategy in heart failure.


2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Jin O-Uchi ◽  
Bong Sook Jhun ◽  
Stephen Hurst ◽  
Shey-Shing Sheu

Introduction: Proline-rich tyrosine kinase 2 (Pyk2) and focal adhesion kinase (FAK) are abundantly expressed in cancer cells. In addition, these kinases are the potent therapeutic targets for cancer treatment and currently several selective FAK/Pyk2 inhibitors are in clinical trials. Recent study revealed that Pyk2 is also highly expressed in heart tissue and significantly activated during human heart failure. We have recently reported that α 1 -adrenoceptor (α 1 -AR) stimulation accelerates mitochondrial Ca 2+ uptake through Pyk2-dependent phospholylation of mitochondrial Ca 2+ uniporter (MCU). However, the roles of Pyk2 in cardiac mitochondrial physiology and pathophysiology have not been well established. Hypothesis: Persistent adrenergic signaling activates cell death signaling via Pyk2-dependent MCU activation and mitochondrial Ca 2+ overload. Methods: Using H9C2 cardiac myoblasts, mitochondrial Ca 2+ and reactive oxygen species (ROS) were measured using mitochondrial matrix-targeted Ca 2+ -sensitive inverse pericam and MitoSOX, respectively. Mitochondrial permeability transition pore (mPTP) activity was observed by measuring the amount of cytochrome c in cytosol by Western blotting or by monitoring the release of GFP-tagged mitochondrial protein, Smac-GFP using confocal microscopy. Results: Pyk2 was not only expressed in cytosol, but also in cardiac mitochondria. α 1 -AR agonist phenylephrine activated mitochondrial Pyk2 and enhanced mitochondrial Ca 2+ uptake via Pyk2-dependent MCU phosphorylation. In addition, persistent α 1 -AR stimulation increases ROS, activity of mPTP. These effects were abolished by co-expression of dominant-negative MCU or kinase-dead Pyk2, suggesting that Pyk2-dependent MCU activation followed by mitochondrial Ca 2+ overload are critical for this mechanism. Moreover, pretreatment of a potent FAK/Pyk2 inhibitor PF-431396 also effectively inhibited α 1 -AR-mediated ROS generation and mPTP activation. Conclusion: FAK/Pyk2 inhibitor prevents mitochondrial Ca 2+ overload, oxidative stress and mitochondrial injury under persistent adrenergic stimulation. Thus, Pyk2 may become a novel potent therapeutic target for preventing cardiac cell injury and death during heart failure.


2019 ◽  
Vol 19 (21) ◽  
pp. 1878-1901 ◽  
Author(s):  
Yue Zhou ◽  
Jian Wang ◽  
Zhuo Meng ◽  
Shuang Zhou ◽  
Jiayu Peng ◽  
...  

Chronic Heart Failure (CHF) is a complex clinical syndrome with a high incidence worldwide. Although various types of pharmacological and device therapies are available for CHF, the prognosis is not ideal, for which, the control of increased Heart Rate (HR) is critical. Recently, a bradycardic agent, ivabradine, is found to reduce HR by inhibiting the funny current (If). The underlying mechanism states that ivabradine can enter the Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and bind to the intracellular side, subsequently inhibiting the If. This phenomenon can prolong the slow spontaneous phase in the diastolic depolarization, and thus, reduce HR. The clinical trials demonstrated the significant effects of the drug on reducing HR and improving the symptoms of CHF with fewer adverse effects. This review primarily introduces the chemical features and pharmacological characteristics of ivabradine and the mechanism of treating CHF. Also, some expected therapeutic effects on different diseases were also concluded. However, ivabradine, as a typical If channel inhibitor, necessitates additional research to verify its pharmacological functions.


Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 618
Author(s):  
Yue Jin ◽  
Shihao Li ◽  
Yang Yu ◽  
Chengsong Zhang ◽  
Xiaojun Zhang ◽  
...  

A mutant of the ridgetail white prawn, which exhibited rare orange-red body color with a higher level of free astaxanthin (ASTX) concentration than that in the wild-type prawn, was obtained in our lab. In order to understand the underlying mechanism for the existence of a high level of free astaxanthin, transcriptome analysis was performed to identify the differentially expressed genes (DEGs) between the mutant and wild-type prawns. A total of 78,224 unigenes were obtained, and 1863 were identified as DEGs, in which 902 unigenes showed higher expression levels, while 961 unigenes presented lower expression levels in the mutant in comparison with the wild-type prawns. Based on Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes analysis, as well as further investigation of annotated DEGs, we found that the biological processes related to astaxanthin binding, transport, and metabolism presented significant differences between the mutant and the wild-type prawns. Some genes related to these processes, including crustacyanin, apolipoprotein D (ApoD), cathepsin, and cuticle proteins, were identified as DEGs between the two types of prawns. These data may provide important information for us to understand the molecular mechanism of the existence of a high level of free astaxanthin in the prawn.


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