Abstract 59: Antimir Therapy Ameliorates HIF1-mediated Loss of SERCA2 and Cardiac Contractility

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Allison L Williams ◽  
Chad Walton ◽  
Keith MacCannell ◽  
Abigail Avelar ◽  
Ralph Shohet
Keyword(s):  
Heart Failure ◽  
Cardiac Contractility ◽  
Hypoxia Inducible Factor ◽  
Heart Tissue ◽  
Ischemic Heart ◽  
Stable Form ◽  
Protein Loss ◽  
Endoplasmic Reticulum Calcium

Ischemic heart disease is a major precipitant of heart failure in the developed world. Hypoxia inducible factor 1 (HIF1) is a highly oxygen-sensitive protein and the principal regulator of hypoxia-related signaling including changes in metabolism and angiogenesis. To more fully understand the role of HIF1 in the heart, our lab has developed a transgenic mouse model in which a stable form of HIF-1alpha can be inducibly expressed under normoxic conditions in cardiomyocytes. Upon HIF1 induction, genes associated with calcium signaling are downregulated and metabolism is shifted toward glycolysis. Strikingly, these mice also show a rapid decrease in cardiac contractility and concurrent loss of SERCA2 protein expression (up to 90%) within one week. SERCA2a (sarcoplasmic/endoplasmic reticulum calcium ATPase 2) is the ATP-dependent calcium pump required for calcium re-uptake during excitation-contraction coupling in the heart and its dysfunction has been implicated in heart failure. To extend the physiological significance of these findings, we examined ischemic heart tissue from WT mice subjected to ligation of the left anterior descending (LAD) artery to mimic myocardial infarction. At one day and 3 days post-ligation, we observed an increase in transcripts needed for glycolysis and decreased abundance of transcripts from the genes for proteins that regulate excitation-contraction including the ryanodine receptor, phospholamban and SERCA2. We also observed that while SERCA2 transcript decreased in HIF1 transgenic hearts, it did not fully account for the observed protein loss. Microarray analysis found miR-29c to be substantially upregulated and a potential regulator of SERCA2 expression. Subsequent in vitro analysis confirmed miR-29c reduced SERCA2 expression by 20-30% and could be modulated with an anti-sense inhibitor. In vivo administration of the antimir to miR-29c also improved cardiac contractility and SERCA2 expression in HIF1 transgenic mice. These results suggest that a HIF1 regulated microRNA, miR-29c, contributes to loss of SERCA2 in hypoxia and can be therapeutically targeted to improve cardiac function.

scholarly journals Slowing of cardiomyocyte Ca2+ release and contraction during heart failure progression in postinfarction mice

2009 ◽  
Vol 296 (4) ◽  
pp. H1069-H1079 ◽  
Author(s):  
Halvor K. Mørk ◽  
Ivar Sjaastad ◽  
Ole M. Sejersted ◽  
William E. Louch
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Shortening Velocity ◽  
Transient Time

Deterioration of cardiac contractility during congestive heart failure (CHF) is believed to involve decreased function of individual cardiomyocytes and may include reductions in contraction magnitude and/or kinetics. We examined the progression of in vivo and in vitro alterations in contractile function in CHF mice and investigated underlying alterations in Ca2+ homeostasis. Following induction of myocardial infarction (MI), mice with CHF were examined at early (1 wk post-MI) and chronic (10 wk post-MI) stages of disease development. Sham-operated mice served as controls. Global and local left ventricle function were assessed by echocardiography in sedated animals (∼2% isoflurane). Excitation-contraction coupling was examined in cardiomyocytes isolated from the viable septum. CHF progression between 1 and 10 wk post-MI resulted in increased mortality, development of hypertrophy, and deterioration of global left ventricular function. Local function in the noninfarcted myocardium also declined, as posterior wall shortening velocity was reduced in chronic CHF (1.2 ± 0.1 vs. 1.9 ± 0.2 cm/s in sham). Parallel alterations occurred in isolated cardiomyocytes since contraction and Ca2+ transient time to peak values were prolonged in chronic CHF (115 ± 6 and 158 ± 11% sham values, respectively). Surprisingly, contraction and Ca2+ transient magnitudes in CHF were larger than sham values at both time points, resulting from increased sarcoplasmic reticulum Ca2+ content and greater Ca2+ influx via L-type channels. We conclude that, in mice with CHF following myocardial infarction, declining myocardial function involves slowing of cardiomyocyte contraction without reduction in contraction magnitude. Corresponding alterations in Ca2+ transients suggest that slowing of Ca2+ release is a critical mediator of CHF progression.

scholarly journals HIF-1 regulation of miR-29c impairs SERCA2 expression and cardiac contractility

2019 ◽  
Vol 316 (3) ◽  
pp. H554-H565 ◽  
Author(s):  
Allison Lesher Williams ◽  
Chad B. Walton ◽  
Keith A. MacCannell ◽  
Abigail Avelar ◽  
Ralph V. Shohet
Keyword(s):  
Heart Failure ◽  
Cellular Response ◽  
Cardiac Contractility ◽  
Hypoxia Inducible Factor ◽  
Stable Form ◽  
Low Oxygen ◽  
Hypoxia Inducible Factor 1 ◽  
Heart Size ◽  
Overexpression System ◽  
Pathological Environment

The principal regulator of cellular response to low oxygen is hypoxia-inducible factor (HIF)-1, which is stabilized in several forms of heart failure. Our laboratory developed a mouse strain in which a stable form of HIF-1 can be inducibly expressed in cardiomyocytes. Strikingly, these mice show a rapid decrease in cardiac contractility and a rapid loss of SERCA2 protein, which is also seen in heart failure. Interestingly, while the SERCA2 transcript decreased, it did not fully account for the observed decrease in protein. We therefore investigated whether HIF-1-regulated microRNA could impair SERCA translation. Multiple screening analyses identified the microRNA miR-29c to be substantially upregulated upon HIF-1 induction and to have complementarity to SERCA, and therefore be a potential regulator of SERCA2 expression in hypoxia. Subsequent evaluation confirmed that miR-29c reduced SERCA2 expression and Ca2+ reuptake. Additionally, administration of an antagonist sequence (antimir) improved cardiac contractility and SERCA2 expression in HIF transgenic mice. To extend the significance of these findings, we examined miR-29c expression in physiological hypoxia. Surprisingly, miR-29c decreased in these settings. We also treated mice with antimir before infarction to see if further suppression of miR-29c could improve cardiac function. While no improvement in contractility or SERCA2 was observed, reduction of heart size after infarction indicated that the antimir could modulate cardiac physiology. These results demonstrate that while a HIF-1-regulated microRNA, miR-29c, can reduce SERCA2 expression and contractility, additional factors in the ischemic milieu may limit these effects. Efforts to develop miRNA-based therapies will need to explore and account for these additional countervailing effects. NEW & NOTEWORTHY Our study demonstrated hypoxia-inducible factor-1-dependent upregulation of miR-29c, which, in turn, inhibited SERCA2 expression and reduced cardiac contractility in a transgenic overexpression system. Interestingly, these results were not recapitulated in a murine myocardial infarction model. These results underscore the complexity of the pathological environment and highlight the need for therapeutic target validation in physiologically relevant models. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/hif1-regulates-mir-29c-and-serca2/ .

Tamarindus indica. Linn leaves ameliorates experimental induced heart failure in Wistar rats

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Hajira Banu Haroon ◽  
Nausheen Ahmed ◽  
Manoj Kumar Sampath ◽  
Supritha Dinesh ◽  
Mohammed Azamthulla ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ethanol Extract ◽  
Serum Levels ◽  
Heart Tissue ◽  
High Dose ◽  
Tamarindus Indica ◽  
Cardiotonic Activity ◽  
Standard Drug

Abstract Objectives Cardiovascular diseases (CVDs) are highly prevalent in various countries, and heart failure accounts for the majority of deaths. The present study focuses on determining the protective effect of ethanol extract of leaves of Tamarindus indica (TIEE) by in vitro and in vivo methods. Methods In vitro cardiotonic activity was determined using Langendorff’s heart perfusion assembly. In vivo studies were performed using Doxorubicin (1.5 mg/kg, i.p for seven days) induced cardiotoxicity in rats. These animals were simultaneously treated with the TIEE at a low dose (200 mg/kg, p.o), high dose (400 mg/kg, p.o) and standard drug Digoxin (100 μg/kg, p.o) for seven days. At the end of the study, various parameters like electrocardiogram (ECG) recording, serum levels of serum glutamic pyruvic transaminase (SGPT), lactate dehydrogenase (LDH), creatinine phosphokinase (CPK), and presence of cardiac troponin (cTnI) were determined. Isolated hearts were subjected to histopathological studies. Results The TIEE at a concentration of 60 μg/mL showed a significant cardiotonic effect in vitro that was evident by increased force of contraction, heart rate, and cardiac output. In vivo studies revealed that the TIEE decreased the prolongation of QT and RR interval of ECG, lowered the serum enzyme levels like LDH, CPK indicating cardiac protection, and the same was established by the absence of cTnI in blood. Histopathological examinations of heart tissue sections showed improved architecture in the treatment groups when compared with diseased groups. Conclusions The study revealed the cardioprotective activity of T. indica leaf extract by both in vitro and in vivo methods.

Abstract 381: Mcur1 is a Potential Target to Modulate Cardiac Contractility and Alleviate Cardiac Function During Heart Failure

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Rajika Roy ◽  
Santhanam Shanmughapriya ◽  
Xueqian Zhang ◽  
Jianliang Song ◽  
Dhanendra Tomar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Dominant Negative ◽  
Selective Channel

Cardiac contractility is regulated by the intracellular Ca 2+ concentration fluxes which are actively regulated by multiple channels and transporters. Ca 2+ uptake into the mitochondrial matrix is precisely controlled by the highly Ca 2+ selective channel, Mitochondrial Calcium Uniporter (MCU). Earlier studies on the cardiac-specific acute MCU knockout and a transgenic dominant-negative MCU mice have demonstrated that mitochondrial Ca 2+ ( m Ca 2+ ) signaling is necessary for cardiac ‘‘fight-or-flight’’ contractile response, however, the role of m Ca 2+ buffering to shape global cytosolic Ca 2+ levels and affect E-C coupling, particularly the Ca 2+ transient, on a beat-to-beat basis still remains to be solved. Our earlier studies have demonstrated that loss of MCU Regulator 1 (MCUR1) in cardiomyocytes results in the impaired m Ca 2+ uptake. We have now employed the cardiac-specific MCUR1 knockout mouse to dissect the precise role of MCU in regulating cytosolic Ca 2+ transients associated with excitation-contraction (E-C) coupling and cardiac function. Results from our studies including the in vivo analyses of cardiac physiology during normal and pressure-overloaded mouse models and in vitro experiments including single-cell cardiac contractility, calcium transients, and electrophysiology measurements demonstrate that MCUR1/MCU regulated m Ca 2+ buffering in cardiomyocytes, although insignificant under basal condition, becomes critical in stress induced conditions and actively participates in regulating the c Ca 2+ transients. Also, the ablation of MCUR1 in cardiomyocytes during stress conditions prevents m Ca 2+ overload and subsequent mROS overproduction. Our data indicate that MCUR1 ablation offers protection against pressure-overload cardiac hypertrophy. In summary, our results provide critical insights into the mechanisms by which the MCU channel contributes in regulating the contractile function of the cardiomyocytes and the role of m Ca 2+ in the development and progression of heart failure.

Adipose Tissue Derived Mesenchymal Stem Cells (ADMSCs) Protect Against Hyperglycemia and Hyperlipidemia Induced Heart Failure by Inhibiting Autophagy Related Apoptosis

2021 ◽  
Author(s):  
Xu Xu ◽  
Sujing Qiang ◽  
Lingyun Tao ◽  
Jie Zhou ◽  
Jing Ni
Keyword(s):  
Heart Failure ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Cardiac Function ◽  
Metabolic Disorder ◽  
Myocardial Cell ◽  
Heart Tissue

Abstract Background Mesenchymal stem cells (MSCs), kinds of seed cells, are expected to improve impaired diabetic cardiac function. Inflammation and autophagy play the important role in the development of metabolic disorder induced heart failure. The aim of this work was to assess the effect of adipose tissue derived mesenchymal stem cells (ADMSCs) on metabolic disorder induced heart failure and the underlying mechanisms. Methods In vivo, 8 weeks old male C57BL/6 mice were randomly divided into three groups: normal chaw mice (sham group), high fat diet fed and streptozotocin intraperitoneal injected mice (HFD + STZ group) and ADMSCs tail intravenous injected per week for 3 months after the mice were treated with HFD + STZ (ADMSCs + HFD + STZ group). The lipid and glucose levels as well as echocardiography were measured per week. Immunohistochemistry was used to detect the adhesion of macrophages in heart tissue among three groups. Besides, inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), interleukin-6 (IL-6) and interleukin-8(CXCL-15) were measured by western blot or RT-qPCR. In vitro, H9c2 cardiomyocytes were stimulated to 33mM glucose in the presence or absence of IL-1β. Transmission electron microscope, mRFG-GFP-LC3 assay and flow cytometry were used to investigate autophagy related apoptosis in H9c2 cells. Results HFD + STZ treated mice presented significant cardiac hypertrophy, body weight loss, hyperglycemia and hyperlipidemia. However, these changes were remarkably reversed by ADMSCs administration. The administration of ADMSCs also remit histological alterations and deposition of collagen in the heart tissue. Furthermore, ADMSCs downregulated the adhesion of macrophages in heart tissue. More importantly, IL-1β from macrophages increased the autophagy of myocardial cell stimulated with high glucose which eventually leaded to their apoptosis and the following cardiac dysfunction. Conclusions This study confirmed that ADMSCs may have potential for use in improving cardiac function by restraining autophagy and apoptosis of myocardial cell. We also found the roles of the IL-1β in hyperglycemia and hyperlipidemia induced cardiac injuries, which may be a key factor for diabetic complications.

scholarly journals The myosin activator omecamtiv mecarbil: a promising new inotropic agent

2016 ◽  
Vol 94 (10) ◽  
pp. 1033-1039 ◽  
Author(s):  
Péter Nánási ◽  
Krisztina Váczi ◽  
Zoltán Papp
Keyword(s):  
Heart Failure ◽  
Mechanism Of Action ◽  
Cardiac Contractility ◽  
Systolic Heart Failure ◽  
Phosphodiesterase Inhibitors ◽  
Inotropic Agent ◽  
Current Therapy ◽  
Omecamtiv Mecarbil

Heart failure became a leading cause of mortality in the past few decades with a progressively increasing prevalence. Its current therapy is restricted largely to the suppression of the sympathetic activity and the renin–angiotensin system in combination with diuretics. This restrictive strategy is due to the potential long-term adverse effects of inotropic agents despite their effective influence on cardiac function when employed for short durations. Positive inotropes include inhibitors of the Na+/K+ pump, β-receptor agonists, and phosphodiesterase inhibitors. Theoretically, Ca2+ sensitizers may also increase cardiac contractility without resulting in Ca2+ overload; nevertheless, their mechanism of action is frequently complicated by other pleiotropic effects. Recently, a new positive inotropic agent, the myosin activator omecamtiv mecarbil, has been developed. Omecamtiv mecarbil binds directly to β-myosin heavy chain and enhances cardiac contractility by increasing the number of the active force-generating cross-bridges, presumably without major off-target effects. This review focuses on recent in vivo and in vitro results obtained with omecamtiv mecarbil, and discusses its mechanism of action at a molecular level. Based on clinical data, omecamtiv mecarbil is a promising new tool in the treatment of systolic heart failure.

scholarly journals THE EXPRESSION OF BRAIN NATRIURETIC PEPTIDE MRNA IS UP-REGULATED IN ISCHEMIC HEART TISSUE IN VIVO AND IN VITRO

2012 ◽  
Vol 59 (13) ◽  
pp. E1398 ◽  
Author(s):  
Weiping Ye ◽  
Daniel Lee ◽  
Aluganti N. Chandrakala ◽  
Sampath Parthasarathy ◽  
Jay Zweier ◽  
...  
Keyword(s):  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Heart Tissue ◽  
Ischemic Heart

scholarly journals Ischemic heart injury leads to HIF1-dependent differential splicing of CaMK2γ

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Allison Lesher Williams ◽  
Chad B. Walton ◽  
Blake Pinell ◽  
Vedbar S. Khadka ◽  
Brandyn Dunn ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Hypoxia Inducible Factor ◽  
Cardiac Injury ◽  
Subcellular Fractionation ◽  
Ischemic Heart ◽  
Calcium Flux ◽  
Calcium Handling ◽  
Stable Form ◽  
Sequencing Data

AbstractIschemic heart disease is a leading cause of heart failure and hypoxia inducible factor 1 (HIF1) is a key transcription factor in the response to hypoxic injury. Our lab has developed a mouse model in which a mutated, oxygen-stable form of HIF1α (HIF-PPN) can be inducibly expressed in cardiomyocytes. We observed rapid cardiac dilation and loss of contractility in these mice due to lower expression of excitation–contraction coupling genes and reduced calcium flux. As alternative splicing plays an underappreciated role in transcriptional regulation, we used RNA sequencing to search for splicing changes in calcium-handling genes of HIF-PPN hearts and compared them to previous sequencing data from a model of myocardial infarction (MI) to select for transcripts that are modified in a pathological setting. We found overlap between genes differentially expressed in HIF-PPN and post-MI mice (54/131 genes upregulated in HIF-PPN hearts at 1 day and/or 3 days post-MI, and 45/78 downregulated), as well as changes in alternative splicing. Interestingly, calcium/calmodulin dependent protein kinase II, gamma (CAMK2G) was alternatively spliced in both settings, with variant 1 (v1) substantially decreased compared to variants 2 (v2) and 3 (v3). These findings were also replicated in vitro when cells were transfected with HIF-PPN or exposed to hypoxia. Further analysis of CAMK2γ protein abundance revealed only v1 was detectable and substantially decreased up to 7 days post-MI. Rbfox1, a splicing factor of CAMK2G, was also decreased in HIF-PPN and post-MI hearts. Subcellular fractionation showed CAMK2γ v1 was found in the nuclear and cytoplasmic fractions, and abundance decreased in both fractions post-MI. Chromatin immunoprecipitation analysis of HIF1 in post-MI hearts also demonstrated direct HIF1 binding to CAMK2G. CaMK2 is a key transducer of calcium signals in both physiological and pathological settings. The predominantly expressed isoform in the heart, CaMK2δ, has been extensively studied in cardiac injury, but the specific role of CaMK2γ is not well defined. Our data suggest that loss of CaMK2γ after MI is HIF1-dependent and may play an important role in the heart’s calcium signaling and transcriptional response to hypoxia.

scholarly journals Recapitulating Cardiac Structure and Function In Vitro from Simple to Complex Engineering

Micromachines ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 386
Author(s):  
Ana Santos ◽  
Yongjun Jang ◽  
Inwoo Son ◽  
Jongseong Kim ◽  
Yongdoo Park
Keyword(s):  
Tissue Engineering ◽  
Extracellular Matrix ◽  
Computational Modeling ◽  
Cardiac Tissue ◽  
Cardiac Development ◽  
Heart Tissue ◽  
Cardiac Tissue Engineering ◽  
Cardiac Cells

Cardiac tissue engineering aims to generate in vivo-like functional tissue for the study of cardiac development, homeostasis, and regeneration. Since the heart is composed of various types of cells and extracellular matrix with a specific microenvironment, the fabrication of cardiac tissue in vitro requires integrating technologies of cardiac cells, biomaterials, fabrication, and computational modeling to model the complexity of heart tissue. Here, we review the recent progress of engineering techniques from simple to complex for fabricating matured cardiac tissue in vitro. Advancements in cardiomyocytes, extracellular matrix, geometry, and computational modeling will be discussed based on a technology perspective and their use for preparation of functional cardiac tissue. Since the heart is a very complex system at multiscale levels, an understanding of each technique and their interactions would be highly beneficial to the development of a fully functional heart in cardiac tissue engineering.

scholarly journals A small molecule HIF-1α stabilizer that accelerates diabetic wound healing

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Guodong Li ◽  
Chung-Nga Ko ◽  
Dan Li ◽  
Chao Yang ◽  
Wanhe Wang ◽  
...  
Keyword(s):  
Wound Healing ◽  
Small Molecule ◽  
Hypoxia Inducible Factor ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Impaired Wound Healing ◽  
Von Hippel Lindau ◽  
Design And Synthesis

AbstractImpaired wound healing and ulcer complications are a leading cause of death in diabetic patients. In this study, we report the design and synthesis of a cyclometalated iridium(III) metal complex 1a as a stabilizer of hypoxia-inducible factor-1α (HIF-1α). In vitro biophysical and cellular analyses demonstrate that this compound binds to Von Hippel-Lindau (VHL) and inhibits the VHL–HIF-1α interaction. Furthermore, the compound accumulates HIF-1α levels in cellulo and activates HIF-1α mediated gene expression, including VEGF, GLUT1, and EPO. In in vivo mouse models, the compound significantly accelerates wound closure in both normal and diabetic mice, with a greater effect being observed in the diabetic group. We also demonstrate that HIF-1α driven genes related to wound healing (i.e. HSP-90, VEGFR-1, SDF-1, SCF, and Tie-2) are increased in the wound tissue of 1a-treated diabetic mice (including, db/db, HFD/STZ and STZ models). Our study demonstrates a small molecule stabilizer of HIF-1α as a promising therapeutic agent for wound healing, and, more importantly, validates the feasibility of treating diabetic wounds by blocking the VHL and HIF-1α interaction.

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