Abstract 519: Talin is Required for Normal Adult Heart Function

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yoshitake Cho ◽  
Ruixia Li ◽  
Ana M Manso ◽  
Robert S Ross
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Cardiac Development ◽  
Heart Function ◽  
Left Ventricular ◽  
Mass Spectrometry Analysis ◽  
Adult Heart ◽  
Spectrometry Analysis ◽  
Functional Changes

Talin (Tln) is a component of muscle costameres that links integrins to other components of the cellular cytoskeleton and plays an important role in maintaining the cellular integrity of cardiac myocytes (CM). There are two talin genes, Tln1 and Tln2, expressed in the heart. Tln1 is ubiquitously expressed, and Tln2 is dominantly expressed in CM. In our previous study, we show that the global deletion of Tln2 in mice (T2KO) caused no structural or functional changes in the heart, presumably because CM Tln1 became up-regulated. However, we found that mice lacking both CM Tln1 and Tln2 exhibit cardiac dysfunction by 4 weeks (w) of age with 100% mortality by 6 months (m), showing Tln plays an essential role in cardiac development and in maintaining cardiac function. In this study, we produced a tamoxifen (Tamo)-inducible mouse model in which Tln1 could be explicitly reduced in the adult CM (T1icKO), and then generate T1icKO:T2KO (T1/2dKO), so that the function of Tln could be assessed in the postnatal heart. T2KO and Tln1/2dKO mice were injected with Tamo at 8w. Echocardiograms were performed to evaluate cardiac function up to 8w post-Tamo injection. While T2KO mice showed normal cardiac function, T1/2dKO exhibited a gradual decrease in function post-Tamo injection. At 8w post-Tamo injection, T1/2dKO mice showed cardiac hypertrophy, fibrosis, and heart failure. To understand the mechanism by which deletion CM talin leads to cardiac dysfunction, left ventricular tissue protein lysates from T2KO and T1/2dKO mice at 4w post-Tamo when cardiac function (echo) and structure were preserved in dKO. The protein lysates were subjected to quantitative mass spectrometry analysis. We found there are 1,100 proteins differentially expressed in T2KO and T1/2dKO hearts. Pathway analysis was performed, and the results showed that proteins involved in vesicle transport, protein folding, and innate immunity are most up-regulated in the T1/2dKO heart. Taken together, our results show that Tln is required for maintaining proper cardiac function in the adult heart. The deletion of Tln in CM results in the up-regulation of multiple intracellular pathways, and we are currently studying the role of each pathway in the pathogenesis of heart failure induced by CM Tln deletion.

Abstract 1213: Cardiac Overexpression of Epac1 in Transgenic Mice Protects Heart from Lipopolysaccharide-induced Cardiac Dysfunction and Inhibits JAK-STAT Pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoshi Okumura ◽  
Yunzhe Bai ◽  
Meihua Jin ◽  
Sayaka Suzuki ◽  
Akiko Kuwae ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cyclic Amp ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Proinflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Stat Pathway

The sympathetic nervous system and proinflammatory cytokines are believed to play independent roles in the pathophysiology of heart failure. However, the recent identification of Epac (exchange protein activated by cyclic AMP), a new cyclic AMP-binding protein that directly activates Rap1, have implicated that there may be a potential cross talk between the sympathetic and cytokine signals. In order to examine the role of Epac in cytokine signal to regulate cardiac function, we have generated transgenic mice expressing the human Epac1 gene under the control of alpha-cardiac myosin heavy chain promoter (Epac1-TG), and examined their response in lipopolysaccharide (LPS)-induced cardiac dysfunction, a well established model for sepsis-induced cardiac dysfunction. Sepsis-induced cardiac dysfunction results from the production of proinflammatory cytokines. At baseline, left ventricular ejection fraction (LVEF) was similar (TG vs. NTG, 67±1.7 vs. 69±2.1%, n =7–9). The degree of cardiac hypertrophy (LV(mg)/tibia(mm)) was also similar at 3 months old (TG vs. NTG 4.0±0.1 vs. 4.2±0.1, n =5–6), but it became slightly but significantly greater in Epac1-TG at 5 month old (TG vs. NTG 4.9±0.1 vs. 4.4±0.1, p< 0.05, n =5–7). LPS (5mg/kg) elicited a significant and robust reduction of LVEF in both Epac1-TG and NTG, but the magnitude of this decrease was much less in Epac1-TG at 6 hr after injection (TG vs. NTG 48±2.4 vs. 57±1.8%, p< 0.01, n =6–9). At 24 hr after injection, cardiac function was restored to the baseline in both Epac1-TG and NTG. We also examined the activation of JAK-STAT pathway at 24 hr after injection. The tyrosine phosphorylation of STAT1 (Tyr701) and STAT3 (Tyr705) in LV, which is an indicator of STAT activation, was reduced to a greater degree in Epac1-TG by 31±8.8% ( p< 0.05, n =4) and 29±5.9% ( p< 0.05, n =7), respectively, relative to that in NTG. Taken together, Epac1 protects the heart from the cytokine-induced cardiac dysfunction, at least in part, through the inhibition of the JAK-STAT pathway, suggesting the beneficial role played by sympathetic signal to antagonize proinflammatory cytokine signal in heart failure.

Abstract 50: Therapeutic Silencing of miRNA-652 Restores Cardiac Function and Attenuates Pathological Remodeling in a Mouse Model of Pressure Overload

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Bianca C Bernardo ◽  
Sally S Nguyen ◽  
Catherine E Winbanks ◽  
Xiao-Ming Gao ◽  
Esther J Boey ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Heart Function ◽  
Pressure Overload ◽  
Post Treatment ◽  
Locked Nucleic Acid ◽  
Luciferase Assay ◽  
Sham Operation

Introduction: Targeting microRNAs differentially regulated in settings of stress and protection could represent a new approach for the treatment of heart failure. miR-652 expression increased in hearts of a cardiac stress mouse model and was downregulated in a model of cardiac protection. Aim: To assess the therapeutic potential of silencing miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Methods: Mice were subjected to a sham operation (n=10) or transverse aortic constriction (TAC, n=14) for 4 weeks to induce hypertrophy and cardiac dysfunction. Mice were subcutaneously administered a locked nucleic acid (LNA)-antimiR-652 or LNA-control. Cardiac function was assessed by echocardiography before and 8 weeks post treatment, followed by molecular and histological analyses. Results: Expression of miR-652 increased in hearts subjected to pressure overload compared to sham operated mice (2.9 fold, n=3-5, P<0.05), but was silenced in hearts of mice administered LNA-antimiR-652 (95% decrease, n=3-7, P<0.05). In mice subjected to pressure overload, inhibition of miR-652 improved cardiac function (29±1% at 4 weeks post TAC compared to 35±1% post treatment, n=7, P<0.001) and attenuated cardiac hypertrophy. Functional and morphologic improvements in hearts of treated mice were associated with reduced cardiac fibrosis, apoptosis, cardiomyocyte size; decreased B-type natriuretic peptide gene expression; and preserved angiogenesis (all P<0.05, n=4-7/group). Mechanistically, we identified Jagged1, a Notch1 ligand, as a direct target of miR-652 by luciferase assay. Jagged1 and Notch1 mRNA were upregulated in hearts of TAC treated mice (1.2-1.7 fold, n=7, P<0.05). Importantly, chronic knockdown of miR-652 was not associated with any notable toxicity in other tissues. Conclusion: Therapeutic silencing of miR-652 protects the heart against pathological cardiac remodeling and improves heart function via mechanisms that are associated with preserved angiogenesis, decreased fibrosis and upregulation of a miR-652 target, Jagged1. These studies provide the first evidence that targeted inhibition of miR-652 could represent an attractive approach for the treatment of heart failure.

scholarly journals Inhibitor of lysyl oxidase improves cardiac function and the collagen/MMP profile in response to volume overload

2018 ◽  
Vol 315 (3) ◽  
pp. H463-H473 ◽  
Author(s):  
Elia C. El Hajj ◽  
Milad C. El Hajj ◽  
Van K. Ninh ◽  
Jason D. Gardner
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Lysyl Oxidase ◽  
Volume Overload ◽  
Left Ventricular ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Primary Role ◽  
Collagen Deposition

The cardiac extracellular matrix is a complex architectural network that serves many functions, including providing structural and biochemical support to surrounding cells and regulating intercellular signaling pathways. Cardiac function is directly affected by extracellular matrix (ECM) composition, and alterations of the ECM contribute to the progression of heart failure. Initially, collagen deposition is an adaptive response that aims to preserve tissue integrity and maintain normal ventricular function. However, the synergistic effects of proinflammatory and profibrotic responses induce a vicious cycle, which causes excess activation of myofibroblasts, significantly increasing collagen deposition and accumulation in the matrix. Furthermore, excess synthesis and activation of the enzyme lysyl oxidase (LOX) during disease increases collagen cross-linking, which significantly increases collagen resistance to degradation by matrix metalloproteinases (MMPs). In the present study, the aortocaval fistula model of volume overload (VO) was used to determine whether LOX inhibition could prevent adverse changes in the ECM and subsequent cardiac dysfunction. The major findings from this study were that LOX inhibition 1) prevented VO-induced increases in left ventricular wall stress; 2) partially attenuated VO-induced ventricular hypertrophy; 3) completely blocked the increases in fibrotic proteins, including collagens, MMPs, and their tissue inhibitors; and 4) prevented the VO-induced decline in cardiac function. It remains unclear whether a direct interaction between LOX and MMPs exists; however, our experiments suggest a potential link between the two because LOX inhibition completely attenuated VO-induced increases in MMPs. Overall, our study demonstrated key cardioprotective effects of LOX inhibition against adverse cardiac remodeling due to chronic VO. NEW & NOTEWORTHY Although the primary role of lysyl oxidase (LOX) is to cross-link collagens, we found that elevated LOX during cardiac disease plays a key role in the progression of heart failure. Here, we show that inhibition of LOX in volume-overloaded rats prevented the development of cardiac dysfunction and improved ventricular collagen and matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles.

scholarly journals Moxibustion Improves Chronic Heart Failure by Inhibiting Autophagy and Inflammation via Upregulation of mTOR Expression

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qingling Li ◽  
Wei Wang ◽  
Qiang Ma ◽  
Ran Xia ◽  
Bing Gao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Cardiac Function ◽  
Heart Function ◽  
Interventricular Septum ◽  
Left Ventricular ◽  
Enzyme Linked Immunosorbent Assay ◽  
Myocardial Inflammation ◽  
Protective Effects ◽  
Inflammatory Reactions

How moxibustion improves chronic heart failure is extremely complex and still unclear. This study aimed to explore whether moxibustion inhibits autophagy and reduces inflammation by regulating mTOR expression to induce myocardial protective effects and alleviate symptoms associated with chronic heart failure. Echocardiography was used to detect cardiac function and cardiac structure of rats, including heart rate (HR), left atrium diameter (LA), left ventricular diameter (LV), left ventricular posterior wall (LVPW), interventricular septum (IVS), ejection fraction (EF), and fractional shortening (FS). BNP and NT-pro BNP levels were measured by enzyme-linked immunosorbent assay (ELISA). Autophagy-associated protein (ATG) genes and mTOR were detected by PCR. The expression of mTOR and phosphorylated-mTOR was detected through western blotting of proteins from myocardial tissue samples. The left ventricular inflammatory response was detected by immunohistochemistry and included ICAM-1, VCAM-1, MMP-2, and MMP-9 expression. The relationship between autophagy and inflammation was analyzed by correlation analysis. The results from echocardiography and ELISA showed that moxibustion could significantly improve heart function and structure. Western blot and PCR results showed that moxibustion treatment elevated mTOR expression. Further, moxibustion could inhibit autophagy and regulate the expression of key autophagy-related genes, including Vps34, ATG3, ATG5, ATG7, ATG12, and ATG13. By contrast, rapamycin could partially reduce the effects of moxibustion. Immunohistochemistry results indicated that moxibustion could reduce myocardial inflammation. Moreover, there was a positive correlation between autophagy and inflammation. Moxibustion can protect cardiac function in rats with heart failure, possibly inhibiting excessive autophagy of cardiomyocytes and reducing inflammatory reactions through the elevation of mTOR expression.

Hypertriglyceridemia in experimental diabetes: relationship to cardiac dysfunction

1994 ◽  
Vol 72 (5) ◽  
pp. 447-455 ◽  
Author(s):  
Brian Rodrigues ◽  
Paul F. Grassby ◽  
Mary L. Battell ◽  
Stephanie Y. N. Lee ◽  
John H. McNeill
Keyword(s):  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Heart Function ◽  
Diabetic Rats ◽  
Left Ventricular ◽  
Plasma Triglyceride ◽  
Diabetic Rat ◽  
Diabetic Patients ◽  
Beneficial Effects ◽  
Rate Of Increase

The incidence of mortality from cardiovascular disease is higher in diabetic patients. The objective of the present investigation was to test die hypothesis that the diabetes-induced depression in cardiac function may be due to hypertriglyceridemia. Hyperlipidemia and a depressed left ventricular developed pressure and rate of increase and decrease of ventricular pressure (±dP/dt) were produced in isolated hearts from rats made diabetic with streptozotocin compared with hearts from control animals. This depressed cardiac performance was successfully prevented by hydralazine treatment (for 3 weeks), which also lowered plasma triglyceride levels and suggested that hyperlipidemia may be important in altering cardiac function in experimental diabetic rats. The beneficial effects of clofibrate, verapamil, prazosin, enalapril, and benazepril administration were then studied in diabetic rats. The treatments (with die exception of enalapril) significantly reduced plasma triglyceride levels but did not prevent die onset of heart dysfunction in chronically diabetic rats. These studies suggest that in the chronically diabetic rat, hypertriglyceridemia may not be as important as previously suggested, in the development of cardiac dysfunction. Since acute dichloroacetate perfusion improves cardiac function in 6 week (but not 24 week) diabetic rats, it appears more likely that improving myocardial glycose utilization is more critical than triglyceride lowering, in preventing cardiac dysfunction in die diabetic rat at this time point.Key words: diabetes, triglycerides, heart function, glucose oxidation.

scholarly journals Protective Effects of Thyroid Hormone Deprivation on Progression of Maladaptive Cardiac Hypertrophy and Heart Failure

2021 ◽  
Vol 8 ◽  
Author(s):  
Helena Kerp ◽  
Georg Sebastian Hönes ◽  
Elen Tolstik ◽  
Judith Hönes-Wendland ◽  
Janina Gassen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Heart Function ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Cardiovascular Morbidity And Mortality ◽  
The Impact

Purpose: Thyroid hormones (TH) play a central role for cardiac function. TH influence heart rate and cardiac contractility, and altered thyroid function is associated with increased cardiovascular morbidity and mortality. The precise role of TH in onset and progression of heart failure still requires clarification.Methods: Chronic left ventricular pressure overload was induced in mouse hearts by transverse aortic constriction (TAC). One week after TAC, alteration of TH status was induced and the impact on cardiac disease progression was studied longitudinally over 4 weeks in mice with hypo- or hyperthyroidism and was compared to euthyroid TAC controls. Serial assessment was performed for heart function (2D M-mode echocardiography), heart morphology (weight, fibrosis, and cardiomyocyte cross-sectional area), and molecular changes in heart tissues (TH target gene expression, apoptosis, and mTOR activation) at 2 and 4 weeks.Results: In diseased heart, subsequent TH restriction stopped progression of maladaptive cardiac hypertrophy and improved cardiac function. In contrast and compared to euthyroid TAC controls, increased TH availability after TAC propelled maladaptive cardiac growth and development of heart failure. This was accompanied by a rise in cardiomyocyte apoptosis and mTOR pathway activation.Conclusion: This study shows, for the first time, a protective effect of TH deprivation against progression of pathological cardiac hypertrophy and development of congestive heart failure in mice with left ventricular pressure overload. Whether this also applies to the human situation needs to be determined in clinical studies and would infer a critical re-thinking of management of TH status in patients with hypertensive heart disease.

Quantification of left ventricular mechanical dyssynchrony by conductance catheter in heart failure patients

2004 ◽  
Vol 286 (2) ◽  
pp. H723-H730 ◽  
Author(s):  
Paul Steendijk ◽  
Sven A. F. Tulner ◽  
Jan J. Schreuder ◽  
Jeroen J. Bax ◽  
Lieselot van Erven ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Mechanical Dyssynchrony ◽  
Left Ventricular ◽  
Conductance Catheter ◽  
Heart Failure Patients ◽  
Optimal Therapy ◽  
Left Ventricular Mechanical Dyssynchrony ◽  
Temporal And Spatial

Mechanical dyssynchrony is an important codeterminant of cardiac dysfunction in heart failure. Treatment, either medical, surgical, or by pacing, may improve cardiac function partly by improving mechanical synchrony. Consequently, the quantification of ventricular mechanical (dys)synchrony may have important diagnostic and prognostic value and may help to determine optimal therapy. Therefore, we introduced new indexes to quantify temporal and spatial aspects of mechanical dyssynchrony derived from online segmental conductance catheter signals obtained during diagnostic cardiac catheterization. To test the feasibility and usefulness of our approach, we determined cardiac function and left ventricular mechanical dyssynchrony by the conductance catheter in heart failure patients with intraventricular conduction delay ( n = 12) and in patients with coronary artery disease ( n = 6) and relatively preserved left ventricular function. The heart failure patients showed depressed systolic and diastolic function. However, the most marked hemodynamic differences between the groups were found for mechanical dyssynchrony, indicating a high sensitivity and specificity of the new indexes. Comparison of conductance catheter-derived indexes with septal-to-lateral dyssynchrony derived by tissue-Doppler velocity imaging showed highly significant correlations. The proposed indexes provide additional, new, and quantitative information on temporal and spatial aspects of mechanical dyssynchrony. They may refine diagnosis of cardiac dysfunction and evaluation of interventions, and ultimately help to select optimal therapy.

Effects of free fatty acids and dichloroacetate on isolated working diabetic rat heart

1991 ◽  
Vol 261 (4) ◽  
pp. H1053-H1059 ◽  
Author(s):  
T. A. Nicholl ◽  
G. D. Lopaschuk ◽  
J. H. McNeill
Keyword(s):  
Fatty Acids ◽  
Heart Rate ◽  
Cardiac Function ◽  
Free Fatty Acids ◽  
Cardiac Dysfunction ◽  
Glucose Oxidation ◽  
Heart Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Diabetic Heart

It is well established that cardiac dysfunction independent of atherosclerosis develops in both humans and animals with diabetes mellitus. The etiology is complex, involving many different processes, one of which may be increased fatty acid utilization and/or a concomitant decrease in glucose utilization by the diabetic heart. We compared control and 6-wk streptozotocin (STZ)-induced diabetic isolated working rat hearts and were able to demonstrate cardiac dysfunction in the diabetic as assessed by depressed heart rate (HR), heart rate peak systolic pressure product (HR.PSP), left ventricular developed pressure (LVDP), and rate of pressure rise (+dP/dt). Paralleling depressed cardiac function in the diabetic were hyperglycemia, hyperlipidemia, and decreased body weight gain compared with age-matched controls. The addition of free fatty acids, in the form of 1.2 mM palmitate, to the isolated working heart perfusate had no effect on either control or diabetic heart function, with the exception of a depressive effect on +dP/dt of diabetic hearts. But diabetic hearts perfused with palmitate-containing perfusate plus the glucose oxidation stimulator dichloroacetate (DCA) showed a marked improvement in function. HR and HR.PSP in spontaneously beating hearts, as well as LVDP and +dP/dt in paced hearts were all restored to control heart values in diabetic hearts perfused in the presence of DCA. Creatine phosphate and ATP levels were similar under all perfusion conditions, thus eliminating energy stores as the limiting factor in heart function. Results indicate that DCA will acutely reverse diabetic cardiac function depression. Therefore glucose oxidation depression in the diabetic heart may be a significant factor contributing to cardiac dysfunction.

scholarly journals Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming

2017 ◽  
Vol 312 (4) ◽  
pp. H768-H780 ◽  
Author(s):  
Kathryn M. Spitler ◽  
Jessica M. Ponce ◽  
Gavin Y. Oudit ◽  
Duane D. Hall ◽  
Chad E. Grueter
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cardiac Function ◽  
Dilated Cardiomyopathy ◽  
Cardiac Development ◽  
Heart Function ◽  
Expression Patterns ◽  
Left Ventricular ◽  
Sequencing Analysis ◽  
Early Lethality

The mediator complex, a multisubunit nuclear complex, plays an integral role in regulating gene expression by acting as a bridge between transcription factors and RNA polymerase II. Genetic deletion of mediator subunit 1 (Med1) results in embryonic lethality, due in large part to impaired cardiac development. We first established that Med1 is dynamically expressed in cardiac development and disease, with marked upregulation of Med1 in both human and murine failing hearts. To determine if Med1 deficiency protects against cardiac stress, we generated two cardiac-specific Med1 knockout mouse models in which Med1 is conditionally deleted (Med1cKO mice) or inducibly deleted in adult mice (Med1cKO-MCM mice). In both models, cardiac deletion of Med1 resulted in early lethality accompanied by pronounced changes in cardiac function, including left ventricular dilation, decreased ejection fraction, and pathological structural remodeling. We next defined how Med1 deficiency alters the cardiac transcriptional profile using RNA-sequencing analysis. Med1cKO mice demonstrated significant dysregulation of genes related to cardiac metabolism, in particular genes that are coordinated by the transcription factors Pgc1α, Pparα, and Errα. Consistent with the roles of these transcription factors in regulation of mitochondrial genes, we observed significant alterations in mitochondrial size, mitochondrial gene expression, complex activity, and electron transport chain expression under Med1 deficiency. Taken together, these data identify Med1 as an important regulator of vital cardiac gene expression and maintenance of normal heart function. NEW & NOTEWORTHY Disruption of transcriptional gene expression is a hallmark of dilated cardiomyopathy; however, its etiology is not well understood. Cardiac-specific deletion of the transcriptional coactivator mediator subunit 1 (Med1) results in dilated cardiomyopathy, decreased cardiac function, and lethality. Med1 deletion disrupted cardiac mitochondrial and metabolic gene expression patterns.

Abstract 129: Inhibition of MEF2 By Atenolol Modifies the Transcriptome During Cardiac Hypertrophy to Improve Heart Function

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Stephanie Wales ◽  
Sara Hashemi ◽  
Keith Dadson ◽  
Subat Tuerdi ◽  
Jian Zhao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Development ◽  
Heart Function ◽  
Myocardial Damage ◽  
Specific Subset ◽  
Adrenergic Antagonist ◽  
Improve Heart Function

Cardiac hypertrophy is a growth response of the adult heart that often results from increased mechanical loading due to high blood pressure and myocardial damage caused by ischemic heart disease. The β1 selective β-adrenergic antagonist, atenolol, is historically one of the most frequently prescribed of all medicines used to preserve heart function following myocardial damage. Transcription factor, myocyte enhancer factor 2 (MEF2), is required for early cardiac development and has also been implicated in cardiac hypertrophy. The effect of β-blockade on the gene program that is activated following cardiac hypertrophy as heart failure progresses is not fully understood. Here we show that treatment with atenolol leads to in vivo changes within the murine heart to reverse cardiac hypertrophy, and this is accompanied by repression of MEF2 activity. Cardiac hypertrophy was simulated using transverse aortic constriction (TAC) for four weeks in a transgenic MEF2-lacZ mouse model, followed by six weeks of vehicle (AT-) or atenolol treatment (AT+). Physiological responses in cardiac function, fibrosis, and cardiomyocyte size in TAC+AT+ mice were consistent with cardiac hypertrophy and demonstrated increased MEF2 activity compared to control (TAC-AT-). Atenolol treatment resulted in an overall improvement in cardiac function of TAC+ mice, showing a decrease in cardiomyocyte size, fibrosis and MEF2 activity. RNA was isolated from the left ventricle of the heart to determine changes in mRNA and lncRNA using RNA-seq. Atenolol reversed the expression of a specific subset of genes and lncRNA that become upregulated by TAC which corresponded to gene ontology terms related to metabolism and the immune system. Together, these data demonstrate that atenolol treatment during cardiac hypertrophy inhibits MEF2 activity and concomitantly leads to improved cardiac function. Thus, inhibition of MEF2 may be necessary to improve or reverse the effects of long-term heart failure.

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