scholarly journals Therapeutic Chemical Screen Identifies Phosphatase Inhibitors to Reconstitute PKB Phosphorylation and Cardiac Contractility in ILK-Deficient Zebrafish

Biomolecules ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 153 ◽  
Author(s):  
Alexander Pott ◽  
Maryam Shahid ◽  
Doreen Köhler ◽  
Christian Pylatiuk ◽  
Karolina Weinmann ◽  
...  
Keyword(s):  
Heart Failure ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Severe Heart Failure ◽  
Mechanical Stretch ◽  
Phosphatase Inhibitors ◽  
Small Compound ◽  
Integrin Linked Kinase ◽  
Pkb Phosphorylation

Patients with inherited dilated cardiomyopathy (DCM) often suffer from severe heart failure based on impaired cardiac contractility leading to increased morbidity and mortality. Integrin-linked kinase (ILK) as a part of the cardiac mechanical stretch sensor was found to be an essential genetic regulator of cardiac contractility. Integrin-linked kinase localizes to z-disks and costameres in vertebrate hearts and regulates the activity of the signaling molecule protein kinase B (PKB/Akt) by controlling its phosphorylation. Despite identification of several potential drug targets in the ILK signaling pathway, pharmacological treatment strategies to restore contractile function in ILK-dependent cardiomyopathies have not been established yet. In recent years, the zebrafish has emerged as a valuable experimental system to model human cardiomyopathies as well as a powerful tool for the straightforward high-throughput in vivo small compound screening of therapeutically active substances. Using the ILK deficient zebrafish heart failure mutant main squeeze (msq), which shows reduced PKB phosphorylation and thereby impaired cardiac contractile force, we identified here, in an automated small compound screen, the protein phosphatase inhibitors calyculin A and okadaic acid significantly restoring myocardial contractile function by reconstituting PKB phosphorylation in msq ILK-deficient zebrafish embryos.

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.

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.

Abstract 1102: Cardiac-Specific Myosin Light Chain Kinase (MLCK), a Third Member of MLCK Family, Potentiates Sarcomere Formation and Cardiac Contraction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jason Y Chan ◽  
Morihiko Takeda ◽  
Laura E Briggs ◽  
Jonathan T Lu ◽  
Nobuo Horikoshi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Smooth Muscle ◽  
Cardiac Hypertrophy ◽  
Light Chain ◽  
Myosin Light Chain Kinase ◽  
Myosin Light Chain ◽  
Contractile Function ◽  
Severe Heart Failure ◽  
Cardiac Contraction

Background: Two myosin light chain kinase (MLCK) proteins, skeletal (encoded by mylk2 gene) and smooth muscle MLCK (encoded by mylk1 gene) have been shown to be expressed in mammals. Human mylk2 has been mapped as a disease locus for familial cardiac hypertrophy (OMIM 606566 ), suggesting that abnormal function of skeletal MLCK stimulates cardiac hypertrophy. While phosphorylation of the putative substrate of skeletal MLCK, myosin light chain 2 (MLC2), is recognized as a key regulator of cardiac contraction, the abundance of skeletal MLCK in the heart is controversial, suggesting the existence of an additional MLCK that is preferentially expressed in cardiac muscle. Methods and Results: We characterized a new kinase named cardiac MLCK that is encoded by a gene homologous to mylk1 and 2 and is specifically expressed in the heart in both atrium and ventricle. Expression of cardiac MLCK was highly regulated by the cardiac homeobox transcription factor, Nkx2.5, in neonatal cardiomyocytes. The overall structure of cardiac MLCK protein is conserved with skeletal and smooth muscle MLCK including putative catalytic and adjacent Ca2+/calmodulin binding domains at the carboxyl-terminus. The amino-terminus is unique without significant homology to other known proteins. Cardiac MLCK phosphorylated MLC2v with a catalytic value of Km=4.3 micro M (Lineweaver-Burk analysis) indicating high affinity of cardiac MLCK to MLC2v, similar to the affinity of skeletal muscle MLCK to skeletal muscle MLC2 and smooth muscle MLCK to smooth muscle MLC2. Adenoviral-mediated overexpression of cardiac MLCK and knockdown of cardiac MLCK using RNAi in cultured cardiomyocytes revealed that cardiac MLCK regulates MLC2v phosphorylation, sarcomere organization and cardiac myocyte contraction. Expression of cardiac MLCK protein was significantly decreased in severe heart failure in vivo (post-myocardial infarction heart failure mouse model). Conclusion: Cardiac MLCK is a new key regulator of cardiac contraction and sarcomere organization. Reduction of cardiac MLCK function leading to decreased phosphorylation of MLC2v may contribute to compromised contractile function in the failing heart.

Abstract 744: Arrhythmogenesis in Heart Failure: Role of Interstitial Fibrosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jorge E Massare ◽  
R. Haris Naseem ◽  
Jeff M Berry ◽  
Farhana Rob ◽  
Joseph A Hill
Keyword(s):  
Heart Failure ◽  
Interstitial Fibrosis ◽  
Systolic Dysfunction ◽  
Ventricular Tachyarrhythmia ◽  
Severe Heart Failure ◽  
Pressure Overload ◽  
Cellular Events ◽  
Action Potential Prolongation

Background: Sudden cardiac death due to ventricular tachyarrhythmia (VT) accounts for a large number of deaths in patients with heart failure. Several cellular events which occur during pathological remodeling of the failing ventricle are implicated in the genesis of VT, including action potential prolongation, dysregulation of intercellular coupling, and fibrosis. Interestingly, transgenic mice over-expressing constitutively active PKD (caPKD) develop severe heart failure without interstitial fibrosis, an otherwise prominent feature of the disease. The goal here was to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing myocardium. Methods and Results: We performed echocardiographic, electrocardiographic, and in vivo electrophysiologic studies in 8 –10 week old caPKD mice (n=12). Similar studies were performed in mice with load-induced heart failure induced by surgical pressure overload (sTAB, n=10), a model of heart failure with prominent interstitial fibrosis. caPKD and sTAB mice showed similar degrees of ventricular dilation (LV systolic dimension caPKD 2.4±0.8 mm vs 3.0±0.9 sTAB, p=0.18) and severe systolic dysfunction (% fractional shortening caPKD 25±11 vs 28±11 sTAB, p=0.62). Yet, caPKD mice showed minimal interstitial fibrosis, comparable to unoperated controls. With the exception of ventricular refractory period, which was higher in caPKD (48±11 msec vs 36±7 TAB and 40±8 WT, p<0.05), other electrocardiographic and electrophysiologic variables were similar among the 3 groups (p=NS), including heart rate, QT duration, and mean VT threshold. As expected, VT (≥3beats) was readily inducible by programmed stimulation in sTAB mice (7/10). By contrast, VT was less inducible in caPKD mice (4/12; p=0.1 vs TAB and <0.05 vs WT), and uninducible in unoperated controls (0/12). VT was polymorphic in both models, but episodes of VT were both slower (VT cycle length caPKD 58±4.0 msec vs 48±1 sTAB, p=0.016) and longer in caPKD mice (caPKD 1.8±0.7 sec vs 0.47±0.3 sTAB, p=0.038). Conclusion: Interstitial fibrosis contributes to the inducibility, maintenance, and rate of VT in heart failure. These findings highlight the importance of anti-remodeling therapies known to target fibrosis in heart disease.

scholarly journals Alterations in Glucose Metabolism During the Transition to Heart Failure: The Contribution of UCP-2

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 552 ◽  
Author(s):  
Hanna Sarah Kutsche ◽  
Rolf Schreckenberg ◽  
Martin Weber ◽  
Christine Hirschhäuser ◽  
Susanne Rohrbach ◽  
...  
Keyword(s):  
Heart Failure ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Contractile Function ◽  
Uncoupling Protein ◽  
Left Ventricular ◽  
Mitochondrial Uncoupling ◽  
Glut 4

The cardiac expression of the mitochondrial uncoupling protein (UCP)-2 is increased in patients with heart failure. However, the underlying causes as well as the possible consequences of these alterations during the transition from hypertrophy to heart failure are still unclear. To investigate the role of UCP-2 mechanistically, expression of UCP-2 was silenced by small interfering RNA in adult rat ventricular cardiomyocytes. We demonstrate that a downregulation of UCP-2 by siRNA in cardiomyocytes preserves contractile function in the presence of angiotensin II. Furthermore, silencing of UCP-2 was associated with an upregulation of glucose transporter type (Glut)-4, increased glucose uptake, and reduced intracellular lactate levels, indicating improvement of the oxidative glucose metabolism. To study this adaptation in vivo, spontaneously hypertensive rats served as a model for cardiac hypertrophy due to pressure overload. During compensatory hypertrophy, we found low UCP-2 levels with an upregulation of Glut-4, while the decompensatory state with impaired function was associated with an increase of UCP-2 and reduced Glut-4 expression. By blocking the aldosterone receptor with spironolactone, both cardiac function as well as UCP-2 and Glut-4 expression levels of the compensated phase could be preserved. Furthermore, we were able to confirm this by left ventricular (LV) biopsies of patients with end-stage heart failure. The results of this study show that UCP-2 seems to impact the cardiac glucose metabolism during the transition from hypertrophy to failure by affecting glucose uptake through Glut-4. We suggest that the failing heart could benefit from low UCP-2 levels by improving the efficiency of glucose oxidation. For this reason, UCP-2 inhibition might be a promising therapeutic strategy to prevent the development of heart failure.

scholarly journals Changes in myofilament proteins, but not Ca2+ regulation, are associated with a high-fat diet-induced improvement in contractile function in heart failure

2011 ◽  
Vol 301 (4) ◽  
pp. H1438-H1446 ◽  
Author(s):  
Y. Cheng ◽  
W. Li ◽  
T. A. McElfresh ◽  
X. Chen ◽  
J. M. Berthiaume ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Expression ◽  
Contractile Function ◽  
Left Ventricular ◽  
Contractile Properties ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cell Shortening ◽  
Regulatory Properties

Pathological conditions such as diabetes, insulin resistance, and obesity are characterized by elevated plasma and myocardial lipid levels and have been reported to exacerbate the progression of heart failure (HF). Alterations in cardiomyocyte Ca2+ regulatory properties and myofilament proteins have also been implicated in contractile dysfunction in HF. However, our prior studies reported that high saturated fat (SAT) feeding improves in vivo myocardial contractile function, thereby exerting a cardioprotective effect in HF. Therefore, we hypothesized that SAT feeding improves contractile function by altering Ca2+ regulatory properties and myofilament protein expression in HF. Male Wistar rats underwent coronary artery ligation (HF) or sham surgery (SH) and were fed normal chow (SHNC and HFNC groups) or a SAT diet (SHSAT and HFSAT groups) for 8 wk. Contractile properties were measured in vivo [echocardiography and left ventricular (LV) cannulation] and in isolated LV cardiomyocytes. In vivo measures of contractility (peak LV +dP/d t and −dP/d t) were depressed in the HFNC versus SHNC group but improved in the HFSAT group. Isolated cardiomyocytes from both HF groups were hypertrophied and had decreased percent cell shortening and a prolonged time to half-decay of the Ca2+ transient versus the SH group; however, SAT feeding reduced in vivo myocyte hypertrophy in the HFSAT group only. The peak velocity of cell shortening was reduced in the HFNC group but not the HFSAT group and was positively correlated with in vivo contractile function (peak LV +dP/d t). The HFNC group demonstrated a myosin heavy chain (MHC) isoform switch from fast MHC-α to slow MHC-β, which was prevented in the HFSAT group. Alterations in Ca2+ transients, L-type Ca2+ currents, and protein expression of sarco(endo)plasmic reticulum Ca2+-ATPase and phosphorylated phospholamban could not account for the changes in the in vivo contractile properties. In conclusion, the cardioprotective effects associated with SAT feeding in HF may occur at the level of the isolated cardiomyocyte, specifically involving changes in myofilament function but not sarcoplasmic reticulum Ca2+ regulatory properties.

Changes in sarcolemmal PLC isoenzymes in postinfarct congestive heart failure: partial correction by imidapril

1999 ◽  
Vol 277 (1) ◽  
pp. H40-H49 ◽  
Author(s):  
Paramjit S. Tappia ◽  
Song-Yan Liu ◽  
Shalini Shatadal ◽  
Nobuakira Takeda ◽  
Naranjan S. Dhalla ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Coronary Occlusion ◽  
Ace Inhibitor ◽  
Contractile Function ◽  
Hydrolytic Activity ◽  
Protein Mass ◽  
Functional Correction ◽  
Partial Correction

We have examined the changes in quantity and activity of cardiac sarcolemmal (SL) phosphoinositide-phospholipase C (PLC)-β1, -γ1, and -δ1 in a model of congestive heart failure (CHF) secondary to large transmural myocardial infarction (MI). We also instituted a late in vivo monotherapy with imidapril, an ANG-converting enzyme (ACE) inhibitor, to test the hypothesis that its therapeutic action is associated with the functional correction of PLC isoenzymes. SL membranes were purified from the surviving left ventricle of rats in a moderate stage of CHF at 8 wk after occlusion of the left anterior descending coronary artery. SL PLC isoenzymes were examined in terms of protein mass and hydrolytic activity. CHF resulted in a striking reduction (to 6–17% of controls) of the mass and activity of γ1- and δ1-isoforms in combination with a significant increase of both PLC β1 parameters. In vivo treatment with imidapril (1 mg/kg body wt, daily, initiated 4 wk after coronary occlusion) improved the contractile function and induced a partial correction of PLCs. The mass of SL phosphatidylinositol 4,5-bisphosphate and the activities of the enzymes responsible for its synthesis were significantly reduced in post-MI CHF and partially corrected by imidapril. The results indicate that profound changes in the profile of heart SL PLC-β1, -γ1, and -δ1 occur in CHF, which could alter the complex second messenger responses of these isoforms, whereas their partial correction by imidapril may be related to the mechanism of action of this ACE inhibitor.

scholarly journals Analysis of Circulating Forms of proBNP and NT-proBNP in Patients with Severe Heart Failure

2008 ◽  
Vol 54 (5) ◽  
pp. 858-865 ◽  
Author(s):  
Angelika Hammerer-Lercher ◽  
Bernhard Halfinger ◽  
Bettina Sarg ◽  
Johannes Mair ◽  
Bernd Puschendorf ◽  
...  
Keyword(s):  
Heart Failure ◽  
Affinity Chromatography ◽  
Western Blotting ◽  
Severe Heart Failure ◽  
Tandem Ms ◽  
Chromatography Method ◽  
Molecular Masses ◽  
Nano Liquid Chromatography ◽  
Inner Diameter

Abstract Background: The specific forms of pro–B-type natriuretic peptide (proBNP) that occur in human blood are not yet clear. We demonstrated the presence of several proBNP forms in human plasma with a new affinity chromatography method that can be used in combination with nano–liquid chromatography electrospray ionization tandem mass spectrometry (nano-LC–ESI–MS/MS). Methods: For affinity chromatography, we coupled Fab′ fragments of polyclonal sheep antibodies specific for N-terminal proBNP (NT-proBNP) epitope 1–21 to silica beads. We connected a column (10 mm × 0.8 mm inner diameter) packed with these beads to a trypsin reactor and used a preconcentrator in combination with a fritless nanospray column to perform MS analyses of proBNP forms in preextracted and non-preextracted samples of plasma from patients with severe heart failure (HF). We used Western blotting in deglycosylation experiments to confirm the shifts in proBNP and NT-proBNP masses. Results: Tandem MS experiments demonstrated the presence of both NT-proBNP and circulating proBNP in preextracted samples of plasma from patients with severe HF, and Western blotting analyses revealed 2 bands of approximately 23 kDa and 13 kDa that shifted after deglycosylation to positions that corresponded to the locations of recombinant proBNP and synthetic NT-proBNP. Conclusions: We obtained clear evidence for circulating proBNP in patients with severe HF and provided the first demonstration of O-glycosylation of NT-proBNP. The higher molecular masses for NT-proBNP and proBNP observed in the Western blotting analyses than those expected from calculations can be explained by O-glycosylation of these peptides in vivo.

Abstract 360: MiR-133 Modulates the Beta1-Adrenergic Receptor Transduction Cascade

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Alessandra Castaldi ◽  
Tania Zaglia ◽  
Vittoria Di Mauro ◽  
Pierluigi Carullo ◽  
Giacomo Viggiani ◽  
...  
Keyword(s):  
Heart Failure ◽  
Nervous System ◽  
Sympathetic Nervous System ◽  
Cardiac Function ◽  
Cardiac Contractility ◽  
Experimental Studies ◽  
Mrna Translation ◽  
Loss Of Function ◽  
Sympathetic Nervous

Rationale: The sympathetic nervous system plays a fundamental role in the regulation of myocardial function. During chronic pressure overload, over-activation of the sympathetic nervous system induces the release of catecholamines, which activate β-adrenergic receptors (βARs) in cardiomyocytes (CMs) and lead to increased heart rate and cardiac contractility. However, chronic stimulation of βARs leads to impaired cardiac function and β-blockers are widely used as therapeutic agents for the treatment of cardiac disease. MiR-133 is highly expressed in the myocardium and is involved in controlling cardiac function through regulation of mRNA translation/stability. Objective: To determine whether miR-133 affects βAR signaling during progression to heart failure. Methods and Results: Based on bioinformatic analysis, β1AR and other components of the β1AR signal transduction cascade, including adenylate cyclase VI and the catalytic subunit of the cAMP-dependent protein kinase A (PKA), were predicted as direct targets of miR-133 and subsequently validated by experimental studies. Consistently, cAMP accumulation and activation of downstream targets were repressed by miR-133 overexpression in both neonatal and adult CMs following selective β1AR stimulation. Furthermore, gain- and loss-of-function studies of miR-133 revealed its role in counteracting the deleterious apoptotic effects caused by chronic β1AR stimulation. This was confirmed in vivo using a novel cardiacspecific TetON-miR-133 inducible transgenic mouse model (Tg133). When subjected to transaortic constriction, Tg133 mice maintained cardiac performance and showed attenuated apoptosis and reduced fibrosis compared to control mice. Conclusions: MiR-133 controls multiple components of the β1AR transduction cascade and is cardioprotective during heart failure.

Abstract 66: Discovery of a Novel Pharmaceutical Class as Potential Heart Failure Treatment

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Tromondae K Feaster ◽  
Jonathan E Hempel ◽  
Charles H Williams ◽  
Audrey Y Frist ◽  
Hyun S Hwang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systolic Function ◽  
Cardiac Contractility ◽  
Induced Pluripotent Stem Cell ◽  
Pde4 Inhibitor ◽  
Camp Content ◽  
Therapeutic Implications ◽  
Chemical Screening ◽  
Wide Range

Utilizing an unbiased in vivo phenotypic chemical screening platform in zebrafish embryos, our laboratory has identified a number of novel compounds with high selectivity for a wide range of cellular targets, including kinases (CK2a, DRAK2, DYRK2 and bone morphogenetic protein receptors), GPCRs (lysophosphatidic acid receptor 1, and extracellular proton sensor), p300 histone acetyltransferase, and phosphodiesterase-4 (PDE4). While the compounds we discovered have therapeutic implications for a wide range of diseases, our translational work has focused on addressing the cardiovascular diseases. Heart failure (HF) is a leading cause of disability and mortality in US, affecting about 6 million Americans, and the incidence of heart failure is anticipated to increase substantially in the coming decades. Yet, current HF pharmaceuticals are palliative, and the outlook for HF drug pipeline is uncertain. Within this backdrop, we recently discovered eggmanone, an extraordinarily selective PDE4 inhibitor which has no known off-target. An usual feature of eggmanone is that it increases cAMP levels specifically in distinct cellular microdomains, without raising the total cellular cAMP content. In isolated mouse cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), eggmanone increases cardiac contractility by targeting a discrete myocyte microdomain without causing significant changes in myocyte calcium cycling. Importantly, eggmanone enhances systolic function in mice with failing hearts without increasing the heart rate. These results raise the exciting possibility that a microdomain-specific PDE4 inhibitor like eggmanone may be useful as an inotropic therapy for HF which avoids the pitfalls of traditional PDE inhibitors, whose utility has been limited by proarrhythmia, tachyphylaxis and cardiotoxicity.

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