scholarly journals Regulatory Mechanism of LINC00152 on Aggravating Heart Failure through Triggering Fibrosis in an Infarcted Myocardium

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Lizhong Song ◽  
Xiujuan Duan ◽  
Xiaojuan Zeng ◽  
Xinglian Duan ◽  
Li Li
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Fibroblasts ◽  
Roc Curves ◽  
Serum Levels ◽  
Cell Counting ◽  
Qrt Pcr ◽  
Infarcted Myocardium ◽  
Diagnostic Potential

Objective. To elucidate the role of LINC00152 in the progression of heart failure following myocardial infarction. Patients and Methods. Serum levels of LINC00152 in acute myocardial infarction (AMI) patients were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) curves were depicted for assessing the diagnostic value of LINC00152 in AMI. Subsequently, an in vivo AMI model was generated in mice. LINC00152 level in a mouse infarcted myocardium was detected. Echocardiogram was conducted to evaluate the influence of LINC00152 on cardiac function in AMI mice. Primary cardiac fibroblasts were isolated from neonatal mice. After knockdown of LINC00152, proliferative and migratory changes in primary cardiac fibroblasts were assessed by cell counting kit-8 (CCK-8) and transwell assay, respectively. The regulatory effect of LINC00152 on Smad7 level was determined by qRT-PCR. Finally, the involvement of Smad7 in LINC00152-regulated proliferative and migratory abilities in primary cardiac fibroblasts was explored by rescue experiments. Results. Serum level of LINC00152 was elevated in AMI patients. ROC curves demonstrated the diagnostic potential of LINC00152 in AMI (95% CI: 0.806-0.940, p = 0.034 ). In myocardial tissues collected from AMI mice, LINC00152 level was higher than those collected from mice of the sham group. LVEF and FS markedly decreased in AMI mice overexpressing LINC00152 on the 4th week of AMI modeling. After knockdown of LINC00152 in primary cardiac fibroblasts, proliferative and migratory abilities were declined, which were abolished by Smad7 intervention. Conclusions. By downregulating Smad7, LINC00152 aggravates heart failure following AMI via promoting the proliferative and migratory abilities in cardiac fibroblasts.

scholarly journals Kallistatin/ serpina3c inhibits fibrosis after myocardial infarction by regulating glycolytic pathway

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
J.J Ji ◽  
Y.U.Y.U Yao
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Transcriptional Activation ◽  
Cardiac Fibroblasts ◽  
Rna Seq ◽  
Funding Sources ◽  
Proliferation And Differentiation ◽  
Key Enzyme

Abstract Background Fibrotic remodeling is the main pathological mechanism of heart failure after infarction. Studies have shown that the serine protease inhibitor Kallistatin/Serpina3c could inhibit the progression of myocardial hypertrophy and fibrosis after myocardial infarction, but the specific mechanism is unknown. Methods and results We used Serpina3c−/− and C57BL/6 mice to construct a MI model in vivo. TGF-β and hypoxia interfered with cardiac fibroblasts (CFs) to construct a fibrosis model in vitro. RNA-seq assessed the effect of Serpina3c knockout on the transcriptome. CCK-8 and BrdU were used to assess cell proliferation. Western blot and qPCR were used to verify the changes of glycolytic enzymes in the sequencing results. Co-IP was used to verify the interaction between Serpina3c and NR4A1. The results showed that Serpina3c expression decreased in the fibrotic tissue of MI heart and in the fibrosis model in vitro. After Serpina3c knockout, the degree of myocardial infarction fibrosis aggravated, and the proliferation and differentiation of CFs increased. Up-regulation of Serpina3c expression in CFs had the opposite effect, suggesting that Serpina3c had the ability to resist myocardial fibrosis. RNA-Seq results showed that glycolysis-related genes were significantly increased after Serpina3c knockout. Among them, the key enzyme of glycolysis, enolase (ENO1), had the largest change, and at the same time, the glycolysis reaction was enhanced. Inhibition of ENO1 can antagonize the promotion of Serpina3c knockout on the proliferation and differentiation of CFs. Activating the activity of NR4A1 could negatively regulate the expression of ENO1 and then inhibited the proliferation and differentiation of CFs. Conclusions Serpina3c inhibited the transcriptional activation of ENO1 by binding to NR4A1, and then reduced the fibrosis after myocardial infarction by inhibiting glycolysis. In short, Serpina3c provides a potential intervention target for the prevention and treatment of heart failure after infarction. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): National Nature Science Foundation of China (No. 81770452) Serpina3c is a key protein in MI.

scholarly journals Myocardial fibrosis reversion via rhACE2-electrospun fibrous patch for ventricular remodeling prevention

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Zeping Qiu ◽  
Jingwen Zhao ◽  
Fanyi Huang ◽  
Luhan Bao ◽  
Yanjia Chen ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Fibrosis ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Cost Effective ◽  
Intramyocardial Injection ◽  
Undesirable Consequence ◽  
Adverse Remodeling

AbstractMyocardial fibrosis and ventricular remodeling were the key pathology factors causing undesirable consequence after myocardial infarction. However, an efficient therapeutic method remains unclear, partly due to difficulty in continuously preventing neurohormonal overactivation and potential disadvantages of cell therapy for clinical practice. In this study, a rhACE2-electrospun fibrous patch with sustained releasing of rhACE2 to shape an induction transformation niche in situ was introduced, through micro-sol electrospinning technologies. A durable releasing pattern of rhACE2 encapsulated in hyaluronic acid (HA)—poly(L-lactic acid) (PLLA) core-shell structure was observed. By multiple in vitro studies, the rhACE2 patch demonstrated effectiveness in reducing cardiomyocytes apoptosis under hypoxia stress and inhibiting cardiac fibroblasts proliferation, which gave evidence for its in vivo efficacy. For striking mice myocardial infarction experiments, a successful prevention of adverse ventricular remodeling has been demonstrated, reflecting by improved ejection fraction, normal ventricle structure and less fibrosis. The rhACE2 patch niche showed clear superiority in long term function and structure preservation after ischemia compared with intramyocardial injection. Thus, the micro-sol electrospun rhACE2 fibrous patch niche was proved to be efficient, cost-effective and easy-to-use in preventing ventricular adverse remodeling.

Abstract 2419: Left Ventricle Function Preservation by a Novel Synthetic Hydrogel Injection in Myocardial Infarction Rabbit

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Xiaoyan Li ◽  
Xuejun Jliang ◽  
Tao Wang ◽  
Taol Lin ◽  
Congxin Huang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Coronary Artery ◽  
Left Ventricle ◽  
Ethylene Glycol ◽  
Control Group ◽  
Coronary Artery Ligation ◽  
Poly Ethylene Glycol ◽  
Infarcted Myocardium ◽  
Poly Ethylene

Myocardial infarction and the subsequent heart failure remain among the world’s prominent health challenges. Other studies have demonstrated that bio-derived materials improve cardiac function after implantation for angiogenic potential. In this study, we hypothesized that injection of biomaterials into infarcted myocardium can preserve left ventricle (LV) function through its prevention of paradoxical systolic bulging. Infarction was induced in rabbit myocardium by coronary artery ligation. In sham-operated rabbits (n = 5), a suture was tied loosely around the left anterior descending coronary artery without ligating it. 7 dayslater, 100μl α-cyclodextrin (CD) solution and 100μl poly (ethylene glycol)-b-polycaprolactone-(dodecanedioic acid)-polycaprolactone-poly (ethylene glycol)(MPEG-PCL-MPEG) solution (n = 7) was injected simultaneously through Duploject applicator into the infarcted myocardium. Solid hydrogel matrix formed by linear MPEG-PCL-MPEG polymer threading into the cavities of the α-cyclodextrin after mixing. Injection of phosphate buffered saline (PBS) served as controls (n = 7). 28 days after the treatments, histological analysis indicated that injection of hydrogel prevented scar expansion and wall thinning compared with group ( P < 0.05) without more microvessel density in infarcted myocardium ( P = 0.70).By echocardiography, LV ejection fraction was significantly greater in the hydrogel group (56.09 ± 8.42%) than the control group (37.26 ± 6.36%, P = 0.001). The LV end-diastolic and end-systolic diameters were 2.07 ± 0.33 cm and 1.74 ± 0.30cm in the control group, respectively. Smaller LV end-diastolic diameter (1.61 ± 0.26cm, P = 0.005) and smaller end-systolic diameter (1.17 ± 0.23cm, P = 0.001) were found in the hydrogel group. These results suggest that α-CD/MPEG-PCL-MPEG hydrogel injection could serve structural and mechanical support of an injured LV replacing some of the functions of the damaged ECM and thus prevented paradoxical motion serves, which may eventually lead to LV remodeling and dilation prevention. Our study should initiate further experimental and clinical studies exploring potential approaches to the treatment of postinfarction heart failure.

Abstract 543: Clinical Development of Cardiac Reprogramming Gene Therapy

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Huanyu Zhou ◽  
Laura M Lombardi ◽  
Christopher A Reid ◽  
Jin Yang ◽  
Chetan Srinath ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Clinical Application ◽  
Cardiac Fibroblasts ◽  
Target Cells ◽  
Large Animal ◽  
Safety And Efficacy ◽  
Treat Heart Failure ◽  
Ability To Regenerate

Heart failure affects an estimated 38 million people worldwide and is typically caused by cardiomyocyte (CM) loss or dysfunction. Although CMs have limited ability to regenerate, a large pool of non-myocytes, including cardiac fibroblasts (CFs), exist in the postnatal heart. In vivo reprogramming of non-myocytes into functional CMs is emerging as a potential new approach to treat heart failure and substantial proof-of-concept has been achieved in this new field. However, challenges remain in terms of clinical application. First, reported human reprogramming cocktails often consist of five to seven factors that require multiple AAV vectors for delivery. Thus, a less complex cocktail that is able to fit into one AAV vector is needed for this technology to impact human health. Second, the lack of specificity in AAV tropism further complicates the safety and regulatory landscape. A means to limit the expression of reprogramming factors to target cells is critical for maximizing long-term safety. Lastly, although promising studies in small animals have already been reported, safety and efficacy results in large animal MI models are critical to justify cardiac reprogramming in human clinical trials. We have developed a novel human cardiac reprogramming cocktail that consists of only two transcription factors and one miRNA. This new cocktail has been engineered into a single AAV cassette to efficiently reprogram human CFs into cardiomyocytes. We also substantially improved transduction of hCFs through AAV capsid engineering and eliminated CMs expression through a microRNA de-targeting method. Moreover, our novel cardiac reprogramming gene therapy improved cardiac function in both rat and swine MI models upon delivery at various time-points after MI without inducing arrhythmias. Given these promising safety and efficacy results in larger animals, we endeavor to translate direct cardiac reprogramming for clinical application.

scholarly journals Cytochrome c oxidase III as a mechanism for apoptosis in heart failure following myocardial infarction

2009 ◽  
Vol 297 (4) ◽  
pp. C928-C934 ◽  
Author(s):  
Changgong Wu ◽  
Lin Yan ◽  
Christophe Depre ◽  
Sunil K. Dhar ◽  
You-Tang Shen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Cytochrome C ◽  
Protein Expression ◽  
Cell Viability ◽  
Cytochrome C Oxidase ◽  
Mitochondrial Gene

Cytochrome c oxidase (COX) is composed of 13 subunits, of which COX I, II, and III are encoded by a mitochondrial gene. COX I and II function as the main catalytic components, but the function of COX III is unclear. Because myocardial ischemia affects mitochondrial oxidative metabolism, we hypothesized that COX activity and expression would be affected during postischemic cardiomyopathy. This hypothesis was tested in a monkey model following myocardial infarction (MI) and subsequent pacing-induced heart failure (HF). In this model, COX I protein expression was decreased threefold after MI and fourfold after HF ( P < 0.05 vs. sham), whereas COX II expression remained unchanged. COX III protein expression increased 5-fold after MI and further increased 10-fold after HF compared with sham ( P < 0.05 vs. sham). The physiological impact of COX III regulation was examined in vitro. Overexpression of COX III in mitochondria of HL-1 cells resulted in an 80% decrease in COX I, 60% decrease in global COX activity, 60% decrease in cell viability, and threefold increase in apoptosis ( P < 0.05). Oxidative stress induced by H2O2 significantly ( P < 0.05) increased COX III expression. H2O2 decreased cell viability by 47 ± 3% upon overexpression of COX III, but only by 12 ± 5% in control conditions ( P < 0.05). We conclude that ischemic stress in vivo and oxidative stress in vitro lead to upregulation of COX III, followed by downregulation of COX I expression, impaired COX oxidative activity, and increased apoptosis. Therefore, upregulation of COX III may contribute to the increased susceptibility to apoptosis following MI and subsequent HF.

Pirfenidone exhibits cardioprotective effects by regulating myocardial fibrosis and vascular permeability in pressure-overloaded hearts

2015 ◽  
Vol 309 (3) ◽  
pp. H512-H522 ◽  
Author(s):  
Kiyoshi Yamagami ◽  
Toru Oka ◽  
Qi Wang ◽  
Takamaru Ishizu ◽  
Jong-Kook Lee ◽  
...  
Keyword(s):  
Heart Failure ◽  
Endothelial Cells ◽  
Vascular Permeability ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Chronic Phase ◽  
Vehicle Group

Although cardiac fibrosis causes heart failure, its molecular mechanisms remain elusive. In this study, we investigated the mechanisms of cardiac fibrosis and examined the effects of the antifibrotic drug pirfenidone (PFD) on chronic heart failure. To understand the responsible mechanisms, we generated an in vivo pressure-overloaded heart failure model via transverse aortic constriction (TAC) and examined the effects of PFD on chronic-phase cardiac fibrosis and function. In the vehicle group, contractile dysfunction and left ventricle fibrosis progressed further from 4 to 8 wk after TAC but were prevented by PFD treatment beginning 4 wk after TAC. We isolated cardiac fibroblasts and vascular endothelial cells from the left ventricles of adult male mice and investigated the cell-type-specific effects of PFD. Transforming growth factor-β induced upregulated collagen 1 expression via p38 phosphorylation and downregulated claudin 5 (Cldn5) expression in cardiac fibroblasts and endothelial cells, respectively; both processes were inhibited by PFD. Moreover, PFD inhibited changes in the collagen 1 and Cldn5 expression levels, resulting in reduced fibrosis and serum albumin leakage into the interstitial space during the chronic phase in TAC hearts. In conclusion, PFD inhibited cardiac fibrosis by suppressing both collagen expression and the increased vascular permeability induced by pressure overload.

scholarly journals Evidence for minimal cardiogenic potential of Sca-1 positive cells in the adult mouse heart

2018 ◽  
Author(s):  
Lauren E. Neidig ◽  
Florian Weinberger ◽  
Nathan J. Palpant ◽  
John Mignone ◽  
Amy M. Martinson ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Mouse Model ◽  
Lineage Tracing ◽  
Mouse Heart ◽  
Genetic Lineage ◽  
Adult Heart ◽  
New Therapeutic Approaches ◽  
Genetic Lineage Tracing

ABSTRACTBackgroundDespite modern pharmacotherapy, heart failure remains a major medical burden. The heart has a limited regenerative capacity, and bolstering regeneration might represent new therapeutic approaches for heart failure patients. Various progenitor cells in the heart have been proposed to have cardiomyogenic properties, but this evidence is based mostly on cell culture and transplantation studies. One population of interest is characterized by the expression of Stem Cell Antigen-1 (Sca-1). Here we tested the hypothesis that Sca-1+cells are endogenous progenitors for cardiomyocytes in the adult heart.MethodsWe evaluated the innate cardiogenic potential of Sca-1+cellsin vivoby generating a novel mouse model to genetically lineage-trace the fate of Sca-1 expressing cells. This was accomplished by introducing a tamoxifen-inducible Cre-recombinase into the Sca-1 locus (Sca-1mCm/+). Crossing this mouse line to a Cre-dependent tdTomato reporter line allowed for genetic lineage-tracing of endogenous Sca-1+cells (Sca-1mCmR26tdTomato). The frequency of Sca-1+cardiomyocytes was quantified from dispersed cell preparations and confirmed by in situ histology.ResultsWe validated the genetic lineage tracing mouse model in bone marrow and heart. Unlike previous publications suggesting significant cardiogenic potential, we found that less than 0.02% of cardiomyocytes per year were derived from Sca-1+cells in the adult heart under homeostatic conditions. At six months after myocardial infarction, we found less than 0.01% of cardiomyocytes were derived from Sca-1+cells.ConclusionOur results show that Sca-1+cells in the adult heart have minimal cardiogenic potential under homeostatic conditions or in response to myocardial infarction.

scholarly journals Cardiac Mesenchymal Cells Cultured at Physiologic Oxygen Tension Have Superior Therapeutic Efficacy in Heart Failure Caused by Myocardial Infarction

2021 ◽  
Vol 9 ◽  
Author(s):  
Robi A. R. Bolli ◽  
Asma Arshia ◽  
Syed A. Hassan ◽  
Chandrashekhar Dasari ◽  
Yibing Nong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Progenitor Cells ◽  
Therapeutic Efficacy ◽  
Therapeutic Potential ◽  
Mesenchymal Cells ◽  
Intraventricular Injection ◽  
Lv Function

Stem/progenitor cells are usually cultured at atmospheric O2 tension (21%); however, since physiologic O2 tension in the heart is ∼5%, using 21% O2 may cause oxidative stress and toxicity. Cardiac mesenchymal cells (CMCs), a newly discovered and promising type of progenitor cells, are effective in improving left ventricle (LV) function after myocardial infarction (MI). We have previously shown that, compared with 21% O2, culture at 5% O2 increases CMC proliferation, telomerase activity, telomere length, and resistance to severe hypoxia in vitro. However, it is unknown whether these beneficial effects of 5% O2in vitro translate into greater therapeutic efficacy in vivo in the treatment of heart failure. Thus, murine CMCs were cultured at 21% or 5% O2. Mice with heart failure caused by a 60-min coronary occlusion followed by 30 days of reperfusion received vehicle, 21% or 5% O2 CMCs via echocardiography-guided intraventricular injection. After 35 days, the improvement in LV ejection fraction effected by 5% O2 CMCs was &gt; 3 times greater than that afforded by 21% O2 CMCs (5.2 vs. 1.5 units, P &lt; 0.01). Hemodynamic studies (Millar catheter) yielded similar results both for load-dependent (LV dP/dt) and load-independent (end-systolic elastance) indices. Thus, two independent approaches (echo and hemodynamics) demonstrated the therapeutic superiority of 5% O2 CMCs. Further, 5% O2 CMCs, but not 21% O2 CMCs, significantly decreased scar size, increased viable myocardium, reduced LV hypertrophy and dilatation, and limited myocardial fibrosis both in the risk and non-infarcted regions. Taken together, these results show, for the first time, that culturing CMCs at physiologic (5%) O2 tension provides superior therapeutic efficacy in promoting cardiac repair in vivo. This concept may enhance the therapeutic potential of CMCs. Further, culture at 5% O2 enables greater numbers of cells to be produced in a shorter time, thereby reducing costs and effort and limiting cell senescence. Thus, the present study has potentially vast implications for the field of cell therapy.

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