Abstract 14834: Protective Role of Cardiomyocyte-derived Ddt in Ischemic Cardiomyopathy

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yina Ma ◽  
Xiaoyue Hu ◽  
Daniel Pfau ◽  
Xiaohong Wu ◽  
Veena Rao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Map Kinase ◽  
Ischemic Cardiomyopathy ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
P38 Map Kinase ◽  
Lv Function ◽  
Acute Ischemia ◽  
S6 Kinase ◽  
Sham Surgery

Background: D-dopachrome tautomerase (DDT), the only homolog of macrophage migration inhibitory factor (MIF), is a cytokine highly expressed in cardiomyocytes and exerts autocrine-paracrine effects by signaling through the CD74 receptor. Endogenous DDT and MIF prevent acute ischemia-reperfusion injury and pressure overload-induced heart failure in mice. This study investigated whether endogenous cardiomyocyte DDT has a role in ischemic cardiomyopathy (ICM). Methods: LV tissue was obtained from patients with ICM during heart transplantation and from non-transplanted donor hearts. Plasma DDT concentrations were measured in heart failure outpatients with ICM. Cardiomyocyte-specific DDT knockout (cKO) and littermate control (CON) mice underwent MI or sham surgery. Serial echocardiography was performed to assess LV remodeling after MI or sham surgery. Tissue from the non-infarct region was analyzed 3 days and 4 weeks after MI or sham surgery for histology and molecular studies. Results: Cardiac DDT mRNA and protein expression were reduced in LV from patients transplanted for ICM (n=8). Plasma DDT concentrations below the median value were associated with worse survival in ICM outpatients (p<0.05, n=32). In mice, baseline LV function was similar in DDT cKO and CON after sham surgery and 3 days post-MI. However, DDT cKO mice developed more rapid LV dilatation and decreased LV ejection fraction and stroke volume as early as 1-week post-MI (n=4-6/group, all P<0.05). The DDT cKO mice had smaller cardiomyocyte cross-sectional area 4 weeks after MI (p <0.05), as well as early diminished phosphorylation of mTOR and S6-kinase (3 days post-MI). They also showed increased apoptosis 3 days post-MI and an early increase in p38 MAP kinase activation. Conclusion: Cardiomyocyte-derived DDT prevents adverse cardiac remodeling in ICM, potentially through modulating mTOR/S6 kinase (adaptive hypertrophy) and p38 MAP kinase (limiting apoptosis). Down-regulation of DDT in patients with ICM may contribute to the pathogenesis of advanced heart failure.

scholarly journals Beneficial Electrophysiological Effects of Rotigaptide Are Unable to Suppress Therapeutic Hypothermia-Provoked Ventricular Fibrillation in Failing Rabbit Hearts With Acute Ischemia–Reperfusion Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Hui-Ling Lee ◽  
Po-Cheng Chang ◽  
Hung-Ta Wo ◽  
Hao-Tien Liu ◽  
Ming-Shien Wen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ventricular Fibrillation ◽  
Therapeutic Hypothermia ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Rabbit Model ◽  
Acute Ischemia ◽  
Electrophysiological Studies ◽  
Electrophysiological Effects

Aims: Whether therapeutic hypothermia (TH) is proarrhythmic in preexisting failing hearts with acute ischemia–reperfusion (IR) injury is unknown. Additionally, the effectiveness of rotigaptide on improving conduction slowing in hearts with IR injury is ambiguous. We investigated the electrophysiological effects of TH and rotigaptide in failing rabbit hearts with acute IR injury and determined the underlying molecular mechanisms.Methods and Results: Heart failure was induced by right ventricular pacing (320 beats/min, 4 weeks). Rabbits with pacing-induced heart failure were randomly divided into TH (n = 14) and non-TH (n = 7) groups. The IR rabbit model was created by ligating the coronary artery for 60 min, followed by reperfusion for 15 min in vivo. Then, the hearts were excised quickly and Langendorff-perfused for simultaneous voltage and intracellular Ca2+ (Cai) optical mapping. Electrophysiological studies were conducted, and vulnerability to ventricular fibrillation (VF) was evaluated using pacing protocols. TH (33°C) was instituted after baseline studies, and electrophysiological studies were repeated. Rotigaptide (300 nM) was infused for 20 min, and electrophysiological studies were repeated under TH. Cardiac tissues were sampled for Western blotting. TH increased the dispersion and beat-to-beat variability of action potential duration (APD), aggravated conduction slowing, and prolonged Cai decay to facilitate spatially discordant alternans (SDA) and VF induction. Rotigaptide reduced the dispersion and beat-to-beat variability of APD and improved slowed conduction to defer the onset of arrhythmogenic SDA by dynamic pacing and elevate the pacing threshold of VF during TH. However, the effect of rotigaptide on TH-enhanced VF inducibility was statistically insignificant. TH attenuated IR-induced dysregulation of protein expression, but its functional role remained uncertain.Conclusion: Therapeutic hypothermia is proarrhythmic in failing hearts with acute IR injury. Rotigaptide improves TH-induced APD dispersion and beat-to-beat variability and conduction disturbance to defer the onset of arrhythmogenic SDA and elevate the VF threshold by dynamic pacing, but these beneficial electrophysiological effects are unable to suppress TH-enhanced VF inducibility significantly.

PREVENTION OF KIDNEY ISCHEMIA-REPERFUSION INJURY: ROLE OF P38 MAP KINASE INHIBITION

2008 ◽  
Vol 86 (Supplement) ◽  
pp. 494
Author(s):  
P Gehwolf ◽  
N Fischler ◽  
R Oberhuber ◽  
C Margreiter ◽  
R Öllinger ◽  
...  
Keyword(s):  
Map Kinase ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
P38 Map Kinase ◽  
Kinase Inhibition ◽  
Kidney Ischemia

scholarly journals Clinical translation of myocardial conditioning

2018 ◽  
Vol 314 (6) ◽  
pp. H1225-H1252 ◽  
Author(s):  
Hans Erik Bøtker ◽  
Thomas Ravn Lassen ◽  
Nichlas Riise Jespersen
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Blood Flow ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Acute Ischemia ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
Flow Restriction

Rapid admission and acute interventional treatment combined with modern antithrombotic pharmacologic therapy have improved outcomes in patients with ST elevation myocardial infarction. The next major target to further advance outcomes needs to address ischemia-reperfusion injury, which may contribute significantly to the final infarct size and hence mortality and postinfarction heart failure. Mechanical conditioning strategies including local and remote ischemic pre-, per-, and postconditioning have demonstrated consistent cardioprotective capacities in experimental models of acute ischemia-reperfusion injury. Their translation to the clinical scenario has been challenging. At present, the most promising mechanical protection strategy of the heart seems to be remote ischemic conditioning, which increases myocardial salvage beyond acute reperfusion therapy. An additional aspect that has gained recent focus is the potential of extended conditioning strategies to improve physical rehabilitation not only after an acute ischemia-reperfusion event such as acute myocardial infarction and cardiac surgery but also in patients with heart failure. Experimental and preliminary clinical evidence suggests that remote ischemic conditioning may modify cardiac remodeling and additionally enhance skeletal muscle strength therapy to prevent muscle waste, known as an inherent component of a postoperative period and in heart failure. Blood flow restriction exercise and enhanced external counterpulsation may represent cardioprotective corollaries. Combined with exercise, remote ischemic conditioning or, alternatively, blood flow restriction exercise may be of aid in optimizing physical rehabilitation in populations that are not able to perform exercise practice at intensity levels required to promote optimal outcomes.

Role of p38 MAP kinase in postcapillary venule leukocyte adhesion induced by ischemia/reperfusion injury

2005 ◽  
Vol 51 (5) ◽  
pp. 463-471 ◽  
Author(s):  
Douglas G. Johns ◽  
Zhaohui Ao ◽  
Robert N. Willette ◽  
Colin H. Macphee ◽  
Stephen A. Douglas
Keyword(s):  
Map Kinase ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
P38 Map Kinase ◽  
Postcapillary Venule

scholarly journals Neuraminidase-1 promotes heart failure after ischemia/reperfusion injury by affecting cardiomyocytes and invading monocytes/macrophages

2020 ◽  
Vol 115 (6) ◽  
Author(s):  
Maren Heimerl ◽  
Irina Sieve ◽  
Melanie Ricke-Hoch ◽  
Sergej Erschow ◽  
Karin Battmer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Connexin 43 ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiomyocyte Hypertrophy ◽  
Lv Function ◽  
Neuraminidase Activity ◽  
Lv Dysfunction ◽  
Inflammatory Macrophages

Abstract Neuraminidase (NEU)1 forms a multienzyme complex with beta-galactosidase (β-GAL) and protective-protein/cathepsin (PPC) A, which cleaves sialic-acids from cell surface glycoconjugates. We investigated the role of NEU1 in the myocardium after ischemia/reperfusion (I/R). Three days after inducing I/R, left ventricles (LV) of male mice (3 months-old) displayed upregulated neuraminidase activity and increased NEU1, β-GAL and PPCA expression. Mice hypomorphic for neu1 (hNEU1) had less neuraminidase activity, fewer pro-inflammatory (Lin−CD11b+F4/80+Ly-6Chigh), and more anti-inflammatory macrophages (Lin−CD11b+F4/80+Ly-6Clow) 3 days after I/R, and less LV dysfunction 14 days after I/R. WT mice transplanted with hNEU1-bone marrow (BM) and hNEU1 mice with WT-BM showed significantly better LV function 14 days after I/R compared with WT mice with WT-BM. Mice with a cardiomyocyte-specific NEU1 overexpression displayed no difference in inflammation 3 days after I/R, but showed increased cardiomyocyte hypertrophy, reduced expression and mislocalization of Connexin-43 in gap junctions, and LV dysfunction despite a similar infarct scar size to WT mice 14 days after I/R. The upregulation of NEU1 after I/R contributes to heart failure by promoting inflammation in invading monocytes/macrophages, enhancing cardiomyocyte hypertrophy, and impairing gap junction function, suggesting that systemic NEU1 inhibition may reduce heart failure after I/R.

Abstract 428: Pharmacologic and Activated Fibroblast-specific Gβγ-GRK2 Inhibition is Protective Following Ischemia Reperfusion Injury

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Joshua G Travers ◽  
Fadia A Kamal ◽  
Michelle L Nieman ◽  
Michelle A Sargent ◽  
Jeffery D Molkentin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Reperfusion Injury ◽  
G Protein ◽  
Knockout Mice ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Ventricular Compliance

Heart failure is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Cardiac fibroblasts are responsible for extracellular matrix homeostasis, however upon injury or pathologic stimulation, these cells transform to a myofibroblast phenotype and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation induces excess signaling through G protein βγ subunits and ultimately the pathologic activation of G protein-coupled receptor kinase 2 (GRK2). We hypothesized that Gβγ-GRK2 inhibition plays an important role in the cardiac fibroblast to attenuate pathologic myofibroblast activation and cardiac remodeling. To investigate this hypothesis, mice were subjected to ischemia/reperfusion (I/R) injury and treated with the small molecule Gβγ-GRK2 inhibitor gallein. While animals receiving vehicle demonstrated a reduction in overall cardiac function as measured by echocardiography, mice treated with gallein exhibited nearly complete preservation of cardiac function and reduced fibrotic scar formation. We next sought to establish the cell specificity of this compound by treating inducible cardiomyocyte- and activated fibroblast-specific GRK2 knockout mice post-I/R. Although we observed modest restoration in cardiac function in cardiomyocyte-specific GRK2 null mice, treatment of these mice with gallein resulted in further protection against myocardial dysfunction following injury, suggesting a functional role in other cardiac cell types, including fibroblasts. Activated fibroblast-specific GRK2 knockout mice were also subjected to ischemia/reperfusion injury; these animals displayed preserved myocardial function and reduced collagen deposition compared to littermate controls following injury. Furthermore, systemic Gβγ-GRK2 inhibition by gallein did not appear to confer further protection over activated fibroblast-specific GRK2 ablation alone. In summary, these findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression.

Abstract 16163: Hydrogen Sulfide Reduces Inflammasome Formation in Mice With Ischemic HFrEF

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Adolfo G Mauro ◽  
Juan Valle Raleigh ◽  
Khoa Nguyen ◽  
David E Durrant ◽  
Erica Kim ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Saline Control ◽  
Lv Function ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Reduced Ejection Fraction ◽  
Fractional Shortening

Background: Hydrogen sulfide (H2S) has been shown to attenuate myocardial ischemia/reperfusion injury via suppression of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. Whether the H2S donor, Na2S, protects against ischemic heart failure with reduced ejection fraction (HFrEF) when treatment is initiated after development of LV dysfunction is unknown. Methods and Results: Adult male mice underwent myocardial infarction (MI) by permanent coronary artery ligation after baseline echocardiography. Repeat echocardiography was performed at day 3 post MI and surviving mice with fractional shortening (FS) less than 25% were treated with either Na2S (100 μg/kg, ip) or saline (volume matched, ip) for 25 days. LV fractional shortening remained unchanged at 7 and 28 days post-MI in the saline group, but improved significantly with Na2S at both time points (Fig. A). Moreover, LV infarct scar size, assessed by trichrome staining, was smaller in Na2S group (14.8 ± 2.1%) as compared to control (28.8 ± 4.8%, P<0.05) at 7 days post MI. Immunofluorescence staining for apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), a component of the inflammasome, showed significant increase at 3 days post MI with sustained elevation at 7 days in the saline-treated group, whereas treatment with Na2S starting on day 3 post-MI significantly attenuated ASC 4 days later (Fig. B). Survival rate was 2-fold higher in Na2S group compared to saline control at 28 days post MI (P<0.05, Fig. C). Conclusion: Treatment with Na2S in mice with ischemic HFrEF improves LV function and survival up to 28 days post MI, possibly through suppression of ASC and prevention of further NLRP3 inflammasome formation. We propose that H2S donors can be promising therapeutic tools for ischemic HF.

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