Abstract 14673: Cardiomyocyte Specific Overexpression of Pellino 1 Reverses Sepsis Induced Cardiac Dysfunction in a Murine Model by Reducing Inflammatory Response and Cardiac Cell Death

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Santosh Swaminathan ◽  
Seetur R. Pradeep ◽  
Rickesha I Wilson ◽  
Jacob Campbell ◽  
Mahesh Thirunavukkarasu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Severe Sepsis ◽  
Cardiac Function ◽  
Genetic Model ◽  
Cecal Ligation ◽  
Tnf Alpha ◽  
Wild Type ◽  
Post Surgery ◽  
Novel Approach ◽  
Cardiac Apoptosis

Introduction: Sepsis remains a significant cause of mortality in the intensive care unit till today. Recent research suggests nearly one in four deaths in people with heart failure is caused by sepsis. Overexpression of mammalian Pellino-1 (Peli1), a E3 ubiquitin ligase, causes inhibition of apoptosis, oxidative stress, and preservation of cardiac function in a myocardial infarction model. Therefore, in the present study, we explored the possibility to overcome sepsis mediated heart failure by overexpressing Peli1 (AMPEL1Tg/+) in a mouse model of severe sepsis. Methods: C57BL/6J (WT) and AMPEL1 Tg/+ mice were divided into Wild-type sham (WTS), Wild-type Cecal Ligation and Puncture (WTCLP), AMPEL1 Tg/+ sham (AMPEL1 Tg/+ S) and AMPEL1 Tg/+ CLP. Cardiac function (LVEF, FS) by two-dimensional echocardiography was assessed pre-procedure, at 6, and 24 hours post-surgery. Serum IL-6 and TNF-alpha (ELISA) at 6 hours and cardiac apoptosis (TUNEL assay) at 24 hours were measured. Results are expressed as mean ± SEM. Results: Analysis of echocardiographic parameters (EF, FS) preoperatively and among the sham groups were similar however there was significant preservation of post-procedure LVEF (%) in the AMPEL1 Tg/+ CLP at the 6 hour (AMPEL1 Tg/+ :52.7 ± 3.71 vs WT:40.7 ±2.46, p=0.013, n=10-11) and 24-hour time point (AMPEL1 Tg/+ :63.1 ± 1.63 vs WT:49.3 ± 4.41, p=0.002, n=9-11) compared to WT. Similar trend was observed in estimation of FS (%) at 6 hours (AMPEL1 Tg/+ :26.3 ± 2.22 vs WT:19.3 ±1.37, p=0.014, n=10-11) and 24 hours (AMPEL1 Tg/+ :32.4 ± 1.89 vs WT:24.4 ± 2.67, p=0.031, n=9-11). A marked decrease in serum IL-6 (AMPEL1 Tg/+ :259.7 ± 18.70 vs WT:483.2 ± 24.01, p<0.0001, n=6, pg/mL) and TNF-alpha (AMPEL1 Tg/+ :86.89 ± 14.36 vs WT:161.8 ± 20, p=0.012, n=6, pg/mL) was observed in the AMPEL1 Tg/+ CLP at 6 hours. The preserved cardiac function in CLP was further supported by a noticeable decrease in cardiac apoptosis (% TUNEL positive cells) at 24 hours in the AMPEL1 Tg/+ CLP group (4.7 ± 0.94 vs 11.7 ± 2.82, p=0.040, n=6,) compared to WTCLP. Conclusions: Thus, Peli1 overexpression is a novel approach that preserved cardiac function, reduced inflammatory markers, and apoptosis following severe sepsis in a murine genetic model.

scholarly journals Delayed activation of caspase-independent apoptosis during heart failure in transgenic mice overexpressing caspase inhibitor CrmA

2010 ◽  
Vol 299 (5) ◽  
pp. H1374-H1381 ◽  
Author(s):  
Soochan Bae ◽  
Parco M. Siu ◽  
Sangita Choudhury ◽  
Qingen Ke ◽  
Jun H. Choi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Caspase Inhibitor ◽  
Wild Type ◽  
Caspase Activation ◽  
Response Modifier ◽  
Specific Expression ◽  
Caspase Inhibition ◽  
Cardiac Apoptosis ◽  
Apoptotic Pathways ◽  
Apoptosis Inducing Factor

Although caspase activation is generally thought to be necessary to induce apoptosis, recent evidence suggests that apoptosis can be activated in the setting of caspase inhibition. In this study, we tested the hypothesis that caspase-independent apoptotic pathways contribute to the development of heart failure in the absence of caspase activation. Acute cardiomyopathy was induced using a single dose of doxorubicin (Dox, 20 mg/kg) injected into male wild-type (WT) and transgenic (Tg) mice with a cardiac-specific expression of cytokine response modifier A (CrmA), a known caspase inhibitor. Early (6 day) survival was significantly better in CrmA Tg (81%) than WT (38%) mice. Twelve days after Dox injection, however, the mortality benefit had dissipated, and increased cardiac apoptosis was observed in both groups. There was, however, a significantly greater release of apoptosis-inducing factor (AIF) from mitochondria to cytosol in CrmA Tg compared with WT mice, which suggests that an enhancement of activation in caspase-independent apoptotic pathways had occurred. The administration of a poly(ADP-ribose) polymerase-1 inhibitor, 4-amino-1,8-naphthalimide (4-AN), to Dox-treated mice resulted in significantly improved cardiac function, a significant blockade of AIF released from mitochondria, and decreased cardiac apoptosis. There were also significantly improved survival in WT (18% without 4-AN vs. 89% with 4-AN) and CrmA Tg (13% without 4-AN vs. 93% with 4-AN) mice 12 days after Dox injection. In conclusion, these findings suggest that apoptosis can be induced in the heart lacking caspase activation via caspase-independent pathways and that enabling the inhibition of AIF activation may provide a significant cardiac benefit.

scholarly journals Vitamin D signaling pathway plays an important role in the development of heart failure after myocardial infarction

2013 ◽  
Vol 114 (8) ◽  
pp. 979-987 ◽  
Author(s):  
Soochan Bae ◽  
Sylvia S. Singh ◽  
Hyeon Yu ◽  
Ji Yoo Lee ◽  
Byung Ryul Cho ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Vitamin D ◽  
Cardiac Function ◽  
Significant Decline ◽  
Vehicle Group ◽  
Wild Type ◽  
Protein Levels ◽  
Vitamin D Analog ◽  
Vitamin D Signaling

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.

Abstract 59: Role of Follistatin 315 in Regulating Cardiac Hypertrophy in Physiology and Pathophysiology

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Zhaobin Xu ◽  
Alisa D Blazek ◽  
Eric Beck ◽  
Jenna Alloush ◽  
Jackie Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Surface ◽  
Cardiac Hypertrophy ◽  
Genetically Modified ◽  
Pressure Overload ◽  
Wild Type ◽  
Surface Binding ◽  
Post Surgery ◽  
Genetically Modified Mice

Heart failure is characterized by initial compensatory changes, including the myocyte hypertrophy, chamber dilation, and matrix remodeling, that proceed until progressive dysfunction produces end stage heart failure and mortality. Recently, the roles of secreted factors in the heart that could regulate pathological hypertrophy, including follistatin (FST) and related molecules, have been examined by various investigators. FST is a molecule that blocks secretion of follicle-stimulating hormone from the pituitary and regulates members of the transforming growth factor beta (TGF-β) family including myostatin. Here we tested the effects of a particular FST isoform, FST288, on heart function in mice. The gene encoding FST produces three isoforms that differ in biological activities and cell surface binding capabilities. The FST315 isoform contains all six exons, and proteolytic cleavage of the FST315 C-terminal tail results in production of FST303. The lack of exon 6, which codes for the acidic C-terminal tail of the putative full-length protein, results in FST288. The missing acidic C-terminal tail region found in soluble FST315 allows FST288 to bind cell surface heparin-sulfated proteoglycans, accounting for the differential actions of these FST isoforms. Since mice that are null for the FST gene die embryonically, we used genetically modified mice that express only the FST288 isoform to test the role of FST315 in adult heart. Examination of these animals suggests that the loss of FST315 expression has limited effects on the heart at the resting state. When these mice are subjected to pressure overload through transverse aortic constriction (TAC) surgery they appear to be resistant to the compensatory cardiac hypertrophy present in wild type mice by 4 weeks post surgery. Both cardiac structure (examined by histology) and function (as measured by echocardiography and pressure/volume loops) following TAC are improved in the genetically modified mice when compared to wild type mice. This response is likely due to modification of the myostatin signaling pathway, one of the major targets of FST315. Overall, our data illustrates that FST315 is an important contributor to the progression of pressure overload induced cardiac hypertrophy.

scholarly journals Initial Characterization of Stressed Transgenic Mice With Cardiomyocyte-Specific Overexpression of Protein Phosphatase 2C

2021 ◽  
Vol 11 ◽  
Author(s):  
Paula Bollmann ◽  
Franziska Werner ◽  
Marko Jaron ◽  
Tom A. Bruns ◽  
Hartmut Wache ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Genetic Model ◽  
Heart Weight ◽  
Adrenergic Stimulation ◽  
Pronounced Increase ◽  
Context Sensitive ◽  
Pathophysiological Role

As part of our ongoing studies on the potential pathophysiological role of serine/threonine phosphatases (PP) in the mammalian heart, we have generated mice with cardiac-specific overexpression of PP2Cβ (PP2C-TG) and compared them with littermate wild type mice (WT) serving as a control. Cardiac fibrosis was noted histologically in PP2C-TG. Collagen 1a, interleukin-6 and the natriuretic peptides ANP and BNP were augmented in PP2C-TG vs. WT (p &lt; 0.05). Left atrial preparations from PP2C-TG were less resistant to hypoxia than atria from WT. PP2C-TG maintained cardiac function after the injection of lipopolysaccharide (LPS, a model of sepsis) and chronic isoproterenol treatment (a model of heart failure) better than WT. Crossbreeding of PP2C-TG mice with PP2A-TG mice (a genetic model of heart failure) resulted in double transgenic (DT) mice that exhibited a pronounced increase of heart weight in contrast to the mild hypertrophy noted in the mono-transgenic mice. The ejection fraction was reduced in PP2C-TG and in PP2A-TG mice compared with WT, but the reduction was the highest in DT compared with WT. PP2A enzyme activity was enhanced in PP2A-TG and DT mice compared with WT and PP2C-TG mice. In summary, cardiac overexpression of PP2Cβ and co-overexpression of both the catalytic subunit of PP2A and PP2Cβ were detrimental to cardiac function. PP2Cβ overexpression made cardiac preparations less resistant to hypoxia than WT, leading to fibrosis, but PP2Cβ overexpression led to better adaptation to some stressors, such as LPS or chronic β-adrenergic stimulation. Hence, the effect of PP2Cβ is context sensitive.

Intracellular mechanisms of specific β-adrenoceptor antagonists involved in improved cardiac function and survival in a genetic model of heart failure

2008 ◽  
Vol 45 (2) ◽  
pp. 240-249 ◽  
Author(s):  
Jan B. Bartholomeu ◽  
Andréa S. Vanzelli ◽  
Natale P.L. Rolim ◽  
Julio C.B. Ferreira ◽  
Luiz R.G. Bechara ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Genetic Model ◽  
Intracellular Mechanisms

scholarly journals Promoting PGC-1α-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts

2014 ◽  
Vol 307 (9) ◽  
pp. H1307-H1316 ◽  
Author(s):  
Georgios Karamanlidis ◽  
Lorena Garcia-Menendez ◽  
Stephen C. Kolwicz ◽  
Chi Fung Lee ◽  
Rong Tian
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Mitochondrial Biogenesis ◽  
Citrate Synthase ◽  
Mitochondrial Gene ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Wild Type ◽  
Term Survival ◽  
Fractional Shortening

Mitochondrial dysfunction in animal models of heart failure is associated with downregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α pathway. To test whether PGC-1α is an appropriate therapeutic target for increasing mitochondrial biogenesis and improving function in heart failure, we used a transgenic (TG) mouse model of moderate overexpression of PGC-1α (∼3-fold) in the heart. TG mice had small increases in citrate synthase activity and mitochondria size in the heart without alterations in myocardial energetics or cardiac function at baseline. In vivo dobutamine stress increased fractional shortening in wild-type mice, but this increase was attenuated in TG mice, whereas ex vivo isolated perfused TG hearts demonstrated normal functional and energetic response to high workload challenge. When subjected to pressure overload by transverse aortic constriction (TAC), TG mice displayed a significantly greater acute mortality for both male and female mice; however, long-term survival up to 8 wk was similar between the two groups. TG mice also showed a greater decrease in fractional shortening and a greater increase in left ventricular chamber dimension in response to TAC. Mitochondrial gene expression and citrate synthase activity were mildly increased in TG mice compared with wild-type mice, and this difference was also maintained after TAC. Our data suggest that a moderate level of PGC-1α overexpression in the heart compromises acute survival and does not improve cardiac function during chronic pressure overload in mice.

scholarly journals Chronic intermittent hypoxia exposure improves left ventricular contractility in transgenic mice with heart failure

2012 ◽  
Vol 113 (5) ◽  
pp. 791-798 ◽  
Author(s):  
Jahan Naghshin ◽  
Rosa H. Rodriguez ◽  
Eric M. Davis ◽  
Lia C. Romano ◽  
Kenneth R. McGaffin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Natriuretic Peptide ◽  
Intermittent Hypoxia ◽  
Left Ventricular ◽  
Unexpected Finding ◽  
Wild Type ◽  
Obstructive Sleep ◽  
The Impact

We previously reported the unexpected finding that 4 wk of exposure to intermittent hypoxia (IH), which simulates the hypoxic stress of obstructive sleep apnea, improved LV cardiac function in healthy, lean C57BL/6J mice. The purpose of the present study was to assess the impact of 4 wk of IH on cardiac function in a transgenic murine model that exhibits a natural history of heart failure. We hypothesized that IH exposure would exacerbate cardiac decompensation in heart failure. Adult male FVB (wild type) and transgenic mice with cardiac overexpression of tumor necrosis factor α (TNF-αTG) at 10–12 wk of age were exposed to 4 wk of IH (nadir inspired oxygen 5–6% at 60 cycles/h for 12 h during light period) or intermittent air (IA) as control. Cardiac function was assessed by echocardiography and pressure-volume loop analyses, and mRNA and protein expression were performed on ventricular homogenates. TNF-αTG mice exposed to IA exhibited impaired LV contractility and increased LV dilation associated with markedly elevated cardiac expression of atrial natriuretic peptide and brain natriuretic peptide compared with wild-type mice. When wild-type FVB mice were exposed to IH, they exhibited increases in arterial pressure and dP/d tmax, consistent with our previous report in C57BL/6J mice. Surprisingly, we found that TNF-αTG mice exposed to IH showed a reduction in end-diastolic volume (38.7 ± 3.8 to 22.2 ± 2.1 ul; P < 0.01) and an increase in ejection fraction (29.4 ± 2.5 to 41.9 ± 3.1%; P < 0.05). In contrast to our previous study in C56Bl/6J mice, neither FVB nor TNF-αTG mice exhibited an upregulation in β-adrenergic expression or cAMP in response to IH exposure. We conclude that 4 wk of exposure to IH in mice induces adaptive responses that improve cardiac function in not only healthy animals but also in animals with underlying heart failure.

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