scholarly journals Decrease of Pdzrn3 is required for heart maturation and protects against heart failure

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Mathieu Pernot ◽  
Béatrice Jaspard-vinassa ◽  
Alice Abelanet ◽  
Sebastien Rubin ◽  
Isabelle Forfar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Polarity ◽  
Nuclear Translocation ◽  
Contractile Function ◽  
Heart Function ◽  
Electric Signal ◽  
Mouse Heart ◽  
Human Heart Failure ◽  
Embryonic Mouse ◽  
Intercalated Disk

AbstractHeart failure is the final common stage of most cardiopathies. Cardiomyocytes (CM) connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between CM. Yet no factor on its own is known to coordinate CM polarized organization. We have previously shown that PDZRN3, an ubiquitine ligase E3 expressed in various tissues including the heart, mediates a branch of the Planar cell polarity (PCP) signaling involved in tissue patterning, instructing cell polarity and cell polar organization within a tissue. PDZRN3 is expressed in the embryonic mouse heart then its expression dropped significantly postnatally corresponding with heart maturation and CM polarized elongation. A moderate CM overexpression of Pdzrn3 (Pdzrn3 OE) during the first week of life, induced a severe eccentric hypertrophic phenotype with heart failure. In models of pressure-overload stress heart failure, CM-specific Pdzrn3 knockout showed complete protection against degradation of heart function. We reported that Pdzrn3 signaling induced PKC ζ expression, c-Jun nuclear translocation and a reduced nuclear ß catenin level, consistent markers of the planar non-canonical Wnt signaling in CM. We then show that subcellular localization (intercalated disk) of junction proteins as Cx43, ZO1 and Desmoglein 2 was altered in Pdzrn3 OE mice, which provides a molecular explanation for impaired CM polarization in these mice. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of CM, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.

scholarly journals Repression of Pdzrn3 is required for heart maturation and protects against heart failure

2020 ◽  
Author(s):  
Mathieu Pernot ◽  
Béatrice Jaspard-vinassa ◽  
Alice Abelanet ◽  
Sebastien Rubin ◽  
Isabelle Forfar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Contractile Function ◽  
Protein Complexes ◽  
Premature Death ◽  
Electric Signal ◽  
Causative Role ◽  
Human Heart Failure ◽  
Mechanical Coupling ◽  
Over Expression ◽  
Anisotropic Conduction

AbstractHeart failure is the final common stage of most cardiopathies. Cardiomyocytes connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between cardiomyocytes. Yet no factor on its own is known to coordinate cardiomyocyte polarized organization. We report enhanced levels of an ubiquitine ligase Pdzrn3 in diseased hypertrophic human and mouse myocardium, which correlates with a loss of cardiomyocyte polarized elongation. We provide evidence that Pdzrn3 has a causative role in heart failure. We found that cardiac Pdzrn3 deficiency protected against heart failure while over expression of Pdzrn3 in mouse cardiomyocytes during the first weeks of life, impaired postnatal cardiomyocyte maturation leading to premature death. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of cardiomyocytes, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.

Abstract 17736: Cardiomyocyte Specific Loss of Diacylglycerol Acyl Transferase 1 (Dgat1) Reproduces the Abnormalities in Lipids Found in Severe Heart Failure

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Chad M Trent ◽  
Li Liu ◽  
Xiang Fang ◽  
Ni-Huiping Son ◽  
Hongfeng Jiang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Function ◽  
Severe Heart Failure ◽  
Fatty Acid Uptake ◽  
Metabolic Effects ◽  
Acid Uptake ◽  
Acyl Transferase ◽  
Human Heart Failure ◽  
Protein Kinase Cα ◽  
Ceramide Content

Diacylglycerol acyl transferase 1 (DGAT1) catalyzes the final step in triglyceride (TG) synthesis, the conversion of diacylglycerol (DAG) to TG. Dgat1-/- mice exhibit a number of beneficial metabolic effects including reduced obesity and improved insulin sensitivity and no known cardiac dysfunction. In contrast, failing human hearts have severely reduced DGAT1 expression associated with accumulation of DAGs and ceramides. To test whether DGAT1 loss alone affects heart function we created cardiomyocyte specific DGAT1 knockout (hDgat1-/-) mice. hDgat1-/- mice hearts had 95% increased DAG and 85% increased ceramides compared to floxed controls. 50% of these mice died by 9 months of age. The heart failure marker brain natriuretic peptide (Bnp) increased 5-fold in hDgat1-/- hearts and fractional shortening (FS) was reduced. This was associated with a 30% increase in PPARalpha and a 40% increase in Cd36. We crossed hDgat1-/- mice with previously described enterocyte-specific Dgat1 knockout mice (hiDgat1-/-). This corrected the early mortality, improved FS 40%, and reduced cardiac ceramide and DAG content. Treatment of hDgat1-/- mice with GLP-1 receptor agonist exenatide for 1 week reduced Bnp mRNA by 50%, improved FS, and reduced heart DAG and ceramide content by 30-40%. Increased fatty acid uptake into hDgat1-/- hearts was normalized by exenatide. Reduced activity of protein kinase Cα (PKCα), which is known to be increased by DAG and ceramides, paralleled the reductions in these lipids. Our mouse studies show that loss of DGAT1 reproduces the lipid abnormalities seen in severe human heart failure.

Abstract 10: Antifibrotic Effect of CCN5 in a Murine Model of Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Dongtak Jeong ◽  
Changwon Kho ◽  
Ahyoung Lee ◽  
Woo Jin Park ◽  
Roger Hajjar
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Western Blot ◽  
Cardiac Fibrosis ◽  
Cell Function ◽  
Heart Function ◽  
Pcr Analysis ◽  
Tgf Beta ◽  
Human Heart Failure ◽  
Ccn Family

CCN family members are matricellular proteins with diverse roles in cell function. Recently, we showed that the differential expression of CCN2 and CCN5 during cardiac remodeling suggests that these two members of the CCN family play opposing roles during the development of cardiac hypertrophy and fibrosis. Since it is reported that an underlying morphological correlate of diastolic dysfunction is cardiac fibrosis, which leads to increased stiffness of the heart, we aimed to evaluate the role of CCN5 on cardiac fibrosis and function by the gene delivery using the cardiotropic AAV9 vector. We generated pressure-overload heart failure models in mouse by TAC operation. After 8-10 weeks of TAC on mice, HF was confirmed by Echocardiography. In those HF mice, AAV9-GFP (control) and AAV9-CCN5 were addressed by IV. Two more months later, cardiac function was evaluated by echocardiography and invasive hemodynamics. Protein and RNA expression levels of CCN5, several types of collagen and conventional TGF-beta signaling related genes were evaluated by western blot and quantitative real time PCR analysis. First, we were able to achieve about 4-5 fold increase of CCN5 expression by AAV9-CCN5 injection without any change in heart function. Second, CCN5 expression level in blood was not significantly altered after AAV9-CCN5 gene transfer because it may be the result of the cardiac tropism of the vector used. The HF model by TAC surgery was confirmed with echocardiography (FS (%)). Overall average FS (%) in HF was 41.87+/− 5.27 (n=16) and in non-surgery control mice was 58.39 +/− 2.06(n=4). After AAV9 injection, cardiac function of CCN5 injected mice was sustained but AAV9-GFP injected mice showed severe cardiac dysfunction and dilation (AAV-GFP (24.29+/− 9.11) vs AAV-CCN5 (42.66 +/− 4.73)). Third, western blot analysis showed that the downstream effectors, namely TGF-beta signaling pathways were significantly down-regulated in CCN5 injected mice. In addition, fibrotic area of the heart was tremendously reduced. Finally, CCN5 expression is significantly decreased in human heart failure patients compared to those in nonfailing donors. Taken together our data would indicate that CCN5 may be a promising therapeutic target to reduce cardiac fibrosis.

Prospects for the use of thyroid hormones in patients with heart failure

2021 ◽  
Author(s):  
S. M. Pyvоvar ◽  
Yu. S. Rudyk ◽  
О. B. Krоtоva ◽  
L. V. Panina
Keyword(s):  
Heart Failure ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Animal Studies ◽  
Cardiac Tissue ◽  
Contractile Function ◽  
Heart Function ◽  
Experimental Studies ◽  
Tissue Level ◽  
Free Triiodothyronine

Thyroid hormone therapy in the setting of heart failure is still an «open book» today. There are several unanswered questions: the regimen, doses and schedule of the use of thyroid hormones, the consequences of such therapy. At the same time, the presence of a comorbid pathology of the thyroid gland, which requires the appointment of levothyroxine, allows one to partially answer these questions. Thyroid hormones affect the diastolic and systolic functions of the myocardium. Ventricular contractile function is also affected by changes in hemodynamic conditions secondary to thyroid hormones and peripheral vascular tone. Thyroid hormone homeostasis maintains a positive ventricular-arterial ratio, resulting in a favorable balance for heart function. Experimental studies in rats have shown that chronic hypothyroidism alone can eventually lead to heart failure. Other studies suggest a decrease in the level of free triiodothyronine in the myocardium after myocardial infarction or with arterial hypertension due to the activation of type 3 deiodinase, which leads to deactivation of triiodothyronine and thyroxine. To address these issues, the researchers propose conducting multicenter, randomized, placebo-controlled trials to evaluate the effects of thyroxine replacement in patients with chronic heart failure. The review highlights the growing body of evidence from animal studies and small clinical trials that suggests that low thyroid activity at the cardiac tissue level can negatively affect the progression of heart failure and that treatment with thyroid hormones can lead to an improved prognosis.

scholarly journals Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α

2012 ◽  
Vol 302 (4) ◽  
pp. H934-H952 ◽  
Author(s):  
Polina S. Petkova-Kirova ◽  
Barry London ◽  
Guy Salama ◽  
Randall L. Rasmusson ◽  
Vladimir E. Bondarenko
Keyword(s):  
Heart Failure ◽  
Gap Junction ◽  
Ventricular Myocytes ◽  
Mouse Heart ◽  
Intercellular Coupling ◽  
Human Heart Failure ◽  
Tnf Α ◽  
Cycle Lengths ◽  
Factor Α ◽  
Junction Conductance

Transgenic mice overexpressing tumor necrosis factor-α (TNF-α mice) possess many of the features of human heart failure, such as dilated cardiomyopathy, impaired Ca2+ handling, arrhythmias, and decreased survival. Although TNF-α mice have been studied extensively with a number of experimental methods, the mechanisms of heart failure are not completely understood. We created a mathematical model that reproduced experimentally observed changes in the action potential (AP) and Ca2+ handling of isolated TNF-α mice ventricular myocytes. To study the contribution of the differences in ion currents, AP, Ca2+ handling, and intercellular coupling to the development of arrhythmias in TNF-α mice, we further created several multicellular model tissues with combinations of wild-type (WT)/reduced gap junction conductance, WT/prolonged AP, and WT/decreased Na+ current ( INa) amplitude. All model tissues were examined for susceptibility to Ca2+ alternans, AP propagation block, and reentry. Our modeling results demonstrated that, similar to experimental data in TNF-α mice, Ca2+ alternans in TNF-α tissues developed at longer basic cycle lengths. The greater susceptibility to Ca2+ alternans was attributed to the prolonged AP, resulting in larger inactivation of INa, and to the decreased SR Ca2+ uptake and corresponding smaller SR Ca2+ load. Simulations demonstrated that AP prolongation induces an increased susceptibility to AP propagation block. Programmed stimulation of the model tissues with a premature impulse showed that reduced gap junction conduction increased the vulnerable window for initiation reentry, supporting the idea that reduced intercellular coupling is the major factor for reentrant arrhythmias in TNF-α mice.

Myofibroblast Deficiency of LSD1 Alleviates TAC-Induced Heart Failure

2021 ◽  
Author(s):  
Jin-Ling Huo ◽  
Lemin Jiao ◽  
Qi An ◽  
Xiuying Chen ◽  
Yuruo Qi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Transforming Growth Factor ◽  
Heart Function ◽  
Wild Type Mouse ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Ang Ii

Rationale: Histone lysine specific demethylase 1 (LSD1) is an important epigenetic anti-tumor drug target, whose inhibitors are currently in phase Ⅰ/Ⅱ clinical trials. However, the potential side effects of LSD1 inhibition in the progress of cardiac remodeling to heart failure remain to be investigated. Objective: To evaluate the roles of myofibroblast- or cardiomyocyte-specific LSD1 deficiency in pressure overload-induced cardiac remodeling. Methods and Results: Adult mouse cardiac fibroblasts (CFs)，neonatal rat cardiac myocytes (NRCMs) and fibroblasts (NRCFs) were isolated, respectively. The myofibroblast-specific and cardiomyocyte-specific LSD1 inducible knockout mice were then generated. We found that LSD1 was increased not only in human DCM (dilated cardiomyopathy) hearts, but also in wild type mouse heart homogenates and isolated CFs, following 20 weeks of transverse aortic constriction (TAC). The upregulation of LSD1 was also observed in Ang II-treated NRCFs, which was reversed by LSD1 silence or its activity inhibition by ORY-1001. These findings suggested a potential involvement of LSD1 in cardiac remodeling. Importantly, myofibroblast-specific LSD1 inducible knockout in vivo significantly alleviated systolic dysfunction, cardiac hypertrophy and fibrosis, following 6 and 20 weeks of TAC. Mechanistically, through RNA-sequencing and the following western blot analysis, we found that loss of LSD1 in Ang II-induced myofibroblasts not only inhibited the intracellular upregulation of transforming growth factor β1 (TGFβ1), its downstream effectors Smad2/3 phosphorylation, as well as the phosphorylation of p38, ERK1/2 and JNK, but also reduced the supernatant TGFβ1 secretion, which then decreased myocyte hypertrophy in the indirect co-culture model. On the other hand, cardiomyocyte-specific LSD1 inducible knockout in vivo triggered the reprogramming of fetal genes, mild cardiac hypertrophy and dysfunction under both basal and stressed conditions. Conclusions: Our findings, for the first time, implicate that myofibroblast-specific LSD1 deletion attenuates TAC-induced cardiac remodeling and improves heart function, suggesting that LSD1 is a potential therapeutic target for late stage heart failure.

Abstract 12606: Autophagy is Required for Mitochondrial Biogenesis in the Heart

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Zhonggang Li ◽  
Quanjiang Zhang ◽  
Karla Pires ◽  
E. Dale Abel
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Contractile Function ◽  
Heart Function ◽  
Early Event ◽  
Acid Oxidation ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Deficient Mice

Autophagy is an essential process that maintains cellular homeostasis via lysosomal degradation pathways. Autophagy has been found to be involved in various pathophysiological conditions in the heart, including myocardial hypertrophy and ischemic heart disease. However, the precise mechanism by which autophagy maintains cardiac function in the non-stressed heart is incompletely understood. We generated cardiac-specific ATG3 deficient mice (cATG3 KO mice) by crossing αMHC-Cre mice with floxed ATG3 mice. Relative to their wild type (WT) littermates, cATG3 KO mice revealed reduced ATG3 expression and inhibited autophagy specifically in the heart. At 4 months of age, cATG3 KO mice showed impaired cardiac contractile function, characterized by a 25% reduction in fractional shortening by echocardiography (p <0.01), Moreover, cATG3 KO mice revealed increased lipid accumulation, reduced fatty acid oxidation and impaired mitochondrial respirations in the heart, without evidence of fibrosis or inflammation. Mitochondrial dysfunction in cATG3 KO mice was accompanied with mitochondrial content loss and reduced expression of mitochondrial biogenesis related genes (PGC1α, NRF1, NRF2 and TFAM). Interestingly, autophagy inhibition, induced mitochondrial biogenesis defects and mitochondrial dysfunction in neonatal cATG3 KO mice (1 week old), prior to the onset of cardiac contractile dysfunction and heart failure, suggesting that cardiac mitochondrial dysfunction may be an early event in the progression of heart failure in the autophagy deficient mice. Finally, in response to exercise training mitochondrial biogenesis (PGC1 alpha induction and increased respiration rates) was completely inhibited in ATG3 deficient mice. In conclusion, autophagy is essential for generating signals that promote mitochondrial biogenesis, and is indispensable for normal heart function under basal conditions.

Abstract 185: Tripartite Motif E3 Ubiquitin Ligase Family Proteins Regulate Intracellular Signaling During the Progression of Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Jenna Alloush ◽  
Eric X Beck ◽  
Sayak Bhattacharya ◽  
Zhaobin Xu ◽  
Liubov Guschina ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Intracellular Signaling ◽  
Heart Function ◽  
Major Complication ◽  
Akt Signaling ◽  
Mouse Heart ◽  
Pi3k Signaling ◽  
Signaling Mechanisms ◽  
Tripartite Motif

Heart failure is a major complication of cardiovascular disease that frequently involves initial cardiac hypertrophy that provides transient compensation for decreased heart function. Eventually, decompensation leads to compromised cardiac structure and progression into heart failure. Investigation of the downstream effector pathways for these growth factors has identified molecules involved in the progression of cardiac hypertrophy and heart failure, including phosphoinositide 3-kinase (PI3K) and Akt (Protein Kinase B). MG53, a tripartite motif (TRIM) protein family member designated as TRIM72, is highly expressed in skeletal and cardiac muscle and is known to have cardioprotective effects through modulation of PI3K signaling mechanisms. It is essential for the activation of PI3K-mediated intracellular signaling in cardiomyocytes and TRIM72 overexpression is sufficient to induce PI3K signaling. As TRIM72 regulates PI3K signaling it may play a role in regulation of heart failure, which is supported by our findings that TRIM72 levels increase in the failing mouse heart. Our recent studies also show that TRIM72 can form heterodimers with other members of the TRIM family proteins that contains approximately 70 different members in the human genome. Many TRIM family proteins are known to act as E3 ubiquitin ligases that target the ubiquitin proteasome to particular proteins. Through this activity, TRIM72 homodimers and heterodimers can resolve specific substrates that can modulate aspects of the PI3K/Akt signaling cascade. Our recent studies have resolved multiple binding partners for TRIM72 in the TRIM family that are co-regulated during heart failure. Resolving the target substrates of the heterodimers formed by these various family members and determining their role in regulating PI3K/Akt signaling mechanisms during cardiac hypertrophy will be further defined as our studies continue.

Abstract 263: A Decline in Kidney-derived Protein Klotho Contributes to Aging-related Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Zhongjie Sun ◽  
Kai Chen
Keyword(s):  
Heart Failure ◽  
Therapeutic Strategy ◽  
Contractile Function ◽  
Heart Function ◽  
Heart Diseases ◽  
Daily Injection ◽  
Aged Mice ◽  
Adult Mice ◽  
Effective Therapeutic Strategy ◽  
Klotho Protein

Background & Objective: The heart function declines in the aged population. At age 80 years, LV contractile function is less than half of what it was at age 20 years. Aging is a recognized risk factor for heart diseases. For instance, the prevalence of heart disease increases with age. The mortality from heart diseases is higher in the aged than in the young population. Klotho is a recently discovered anti-aging gene that is primarily expressed in kidneys. The secreted Klotho is released into blood. The objective of this study is to investigate if a decline serum Klotho levels contributes to aging-related heart failure. Method & Results: The results showed that ejection fraction, stroke volume and cardiac output were decreased in aged mice (24 months) vs. the adult mice (10 months), indicating that aging impairs heart function. The serum level of Klotho was decreased significantly in aged mice. Interestingly, daily injection of recombinant Klotho protein rescued the aging-related decline in heart function. Mutation of Klotho gene ( KL -/- ) resulted in heart failure which was associated with a significant increase in serum phosphate levels (hyperphosphatemia). Low phosphate diet delayed but did not prevent the development of heart failure in male KL -/- mice, suggesting that hyperphosphatemia partially contributes to Klotho deficiency-induced heart failure. Unfortunately, low phosphate diet failed to improve heart failure in female KL -/- mice. Interestingly, administration of estrogen decreased hyperphosphatemia and delayed the development of heart failure in KL -/- although it did not prevent Klotho deficiency-induced heart failure. Therefore, Conclusion: Klotho deficiency contributes to aging-related heart failure. Hyperphosphatemia accelerated the development of Klotho deficiency-induced heart failure. Administration of recombinant Klotho protein is an effective therapeutic strategy for heart aging. (supported by NIH R01 HL118558, AG049780, DK093403).

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