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Keywords: Editorials; endoplasmic reticulum; genetic therapy; hypertrophy, left ventricular; inflammation; sarcoplasmic reticulum; SERCA2a EN Editorials endoplasmic reticulum genetic therapy hypertrophy, left ventricular inflammation sarcoplasmic reticulum SERCA2a 1241 1243 3 06/06/22 20211012 NES 211012 B Article, see p 1227 b The prevailing concept that inflammation is harmful and precipitates transition from pressure overload-mediated hypertrophy to heart failure is supported by studies demonstrating the adverse effects of proinflammatory cytokines on contractile function in cardiomyocytes and their negative inotropic effects in the heart. The immediate translational relevance of these findings is supported by observations from patients with aortic stenosis undergoing transcatheter aortic valve intervention: MYDGF levels were higher in patients than in age- and sex-matched controls and 3 months after valve intervention, levels declined and were comparable to those in controls. Although swimming was effective at stimulating left ventricular hypertrophy, MYDGF levels were not increased, suggesting that both the magnitude and duration of pressure overload were key determinants of inflammatory cell secretion of MYDGF. [Extracted from the article]

Background: Human (h) embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) serve as a potential unlimited ex vivo source of cardiomyocytes (CMs). However, a well-accepted roadblock has been their immature phenotype. hESC/iPSC-derived ventricular (v) CMs and their engineered cardiac microtissues (hvCMTs) similarly displayed positive chronotropic but null inotropic responses to β-adrenergic stimulation. Given that phospholamban (PLB) is robustly present in adult but poorly expressed in hESC/iPSC-vCMs and its defined biological role in β-adrenergic signaling, we investigated the functional consequences of PLB expression in hESC/iPSC-vCMs and hvCMTs.Methods and Results: First, we confirmed that PLB protein was differentially expressed in hESC (HES2, H9)- and iPSC-derived and adult vCMs. We then transduced hES2-vCMs with the recombinant adenoviruses (Ad) Ad-PLB or Ad-S16E-PLB to overexpress wild-type PLB or the pseudophosphorylated point-mutated variant, respectively. As anticipated from the inhibitory effect of unphosphorylated PLB on sarco/endoplasmic reticulum Ca2+-ATPase, Ad-PLB transduction significantly attenuated electrically evoked Ca2+ transient amplitude and prolonged the 50% decay time. Importantly, Ad-PLB-transduced hES2-vCMs uniquely responded to isoproterenol. Ad-S16E-PLB-transduced hES2-vCMs displayed an intermediate phenotype. The same trends were observed with H9- and iPSC-vCMs. Directionally, similar results were also seen with Ad-PLB-transduced and Ad-S16E-transduced hvCMTs. However, Ad-PLB altered neither the global transcriptome nor ICa,L, implicating a PLB-specific effect.Conclusions: Engineered upregulation of PLB expression in hESC/iPSC-vCMs restores a positive inotropic response to β-adrenergic stimulation. These results not only provide a better mechanistic understanding of the immaturity of hESC/iPSC-vCMs but will also lead to improved disease models and transplantable prototypes with adult-like physiological responses. [ABSTRACT FROM AUTHOR]

We have shown that BNIP3 expression is significantly increased in heart failure (HF). In this study, we tested the effects of BNIP3 manipulation in HF.In a rat model of pressure overload HF, BNIP3 knockdown significantly decreased left ventricular (LV) volumes with significant improvement in LV diastolic and systolic function. There were significant decreases in myocardial apoptosis and LV interstitial fibrosis. Ultrastructurally, BNIP3 knockdown attenuated mitochondrial fragmentation and restored mitochondrial morphology and integrity. On the molecular level, there were significant decreases in endoplasmic reticulum (ER) stress and mitochondrial apoptotic markers. One of the mechanisms by which BNIP3 mediates mitochondrial dysfunction is via the oligomerization of the voltage-dependent anion channels causing a shift of calcium from the ER to mitochondrial compartments, leading to the decrease in ER calcium content, mitochondrial damage, apoptosis, and LV interstitial fibrosis, and hence contributes to both systolic and diastolic myocardial dysfunction, respectively. In systolic HF, the downregulation of SERCA2a (sarcoplasmic-endoplasmic reticulum calcium ATPase), along with an increased BNIP3 expression, further worsen myocardial diastolic and systolic function and contribute to the major remodeling seen in systolic HF as compared with diastolic HF with normal SERCA2a expression.The increase in BNIP3 expression contributes mainly to myocardial diastolic dysfunction through mitochondrial apoptosis, LV interstitial fibrosis, and to some extent to myocardial systolic dysfunction attributable to the shift of calcium from the ER to the mitochondria and to the decrease in ER calcium content. However, SERCA2a downregulation remains a prerequisite for the major LV remodeling seen in systolic HF. [ABSTRACT FROM AUTHOR]

Heart failure is characterized by impaired function and disturbed Ca2+ homeostasis. Transgenic increases in inhibitor-1 activity have been shown to improve Ca2 cycling and preserve cardiac performance in the failing heart. The aim of this study was to evaluate the effect of activating the inhibitor (I-1c) of protein phosphatase 1 (I-1) through gene transfer on cardiac function in a porcine model of heart failure induced by myocardial infarction.Myocardial infarction was created by a percutaneous, permanent left anterior descending artery occlusion in Yorkshire Landrace swine (n=16). One month after myocardial infarction, pigs underwent intracoronary delivery of either recombinant adeno-associated virus type 9 carrying I-1c (n=8) or saline (n=6) as control. One month after myocardial infarction was created, animals exhibited severe heart failure demonstrated by decreased ejection fraction (46.4±7.0% versus sham 69.7±8.5%) and impaired (dP/dt)max and (dP/dt)min. Intracoronary injection of AAV9.I-1c prevented further deterioration of cardiac function and led to a decrease in scar size.In this preclinical model of heart failure, overexpression of I-1c by intracoronary in vivo gene transfer preserved cardiac function and reduced the scar size. [ABSTRACT FROM AUTHOR]

The article discusses the results of a study on the effectiveness of gene therapy in the recovery of sarcolemmal structure after chronic heart failure (CHF). CHF damaged the cardiomyocyte surface morphology and T-tubular structure. Sarcolemmalß2-adrenergic receptors were redistributed while secondary messenger signaling was localized in CHF. The results showed that gene therapy allowed the reappearance of T-tubules in the heart and plasticity of sarcolemmal surface structure.

The article discusses research on the administration of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) gene therapy in chronic heart failure. The study investigated sarcoplasmic reticulum calcium (SR Ca2+) leak and arrhythmogenesis following SERCA2a gene transfer. Implantable electrocardiogram telemetry was used in the in vivo assessment of spontaneous ventricular arrhythmia. Electric reserve remodeling in the restored SERCA2a protein levels brought indirect benefits.

The article focuses on the role of gene delivery of sarcoplasmic reticulum calcium ATPase (SERCA2a) in inhibiting ventricular modeling in mitral regurgitation (MR), a condition that doubles the chances of death in heart failure (HF) patients. The concept is tested through 12 sheep using gene delivery. The study concluded that gene delivery enhances the role of the SERCA2a inhibitor in fixing the ventricles of the heart and reduces the chances of an MR-associated death.

Background: Beat-to-beat alternans of cellular repolarization is closely linked to ventricular arrhythmias in humans. We hypothesized that sarcoplasmic reticulum calcium reuptake by SERCA2a plays a central role in the mechanism of cellular alternans and that increasing SERCA2a gene expression will retard the development of cellular alternans.Methods and Results: In vivo gene transfer of a recombinant adenoviral vector with the transgene for SERCA2a (Ad.SERCA2a) was performed in young guinea pigs. Isolated myocytes transduced with Ad.SERCA2a exhibited improved sarcoplasmic reticulum Ca(2+) reuptake (P<0.05) and were markedly resistant to cytosolic calcium alternans (P<0.05) under repetitive constant action potential clamp conditions (ie, when alternation of action potential duration was prevented), proving that sarcoplasmic reticulum Ca(2+) cycling is an important mechanism in the development of cellular alternans. Similarly, SERCA2a overexpression in the intact heart demonstrated significant resistance to alternation of action potential duration when compared with control hearts (heart rate threshold, 484+/-25 bpm versus 396+/-11 bpm, P<0.01), with no change in action potential duration restitution slope. Importantly, SERCA2a overexpression produced a 4-fold reduction in susceptibility to alternans-mediated ventricular arrhythmias (P<0.05).Conclusions: These data provide new evidence that sarcoplasmic reticulum Ca(2+) reuptake directly modulates susceptibility to cellular alternans. Moreover, SERCA2a overexpression suppresses cellular alternans, interrupting an important pathway to cardiac fibrillation in the intact heart. [ABSTRACT FROM AUTHOR]

The article focuses on a study on the effect of active protein phosphatase-1inhibitor-1(I-1) on basal cardiac function and schemia/reperfusion injury through a mouse model. It states that I-1 activity has enhanced contractile function and sarcoplasmic reticulum Ca 2+ transport. Further, a phosphoproteomic analysis reveals that I-1 activity has contracted the recovery of ischemia/reperfusion injury. It suggests that I-1 activity can be a therapeutic strategy in myocardial infarction.

The article details a study on the role of the protein kinase C interacting cousin of thioredoxin (PICOT) in cardiac hypertrophy. The authors hypothesize that PICOT directly interacts with muscle LIM protein (MLP) via its carboxyl-terminal half and that PICOT may affect calcineurin-nuclear factor of activated T cells (NFAT) signaling through its interaction with MLP. They conclude that PICOT inhibits cardiac hypertrophy largely by negatively regulating calcineurin-NFAT signaling via disruption of the MLP-calcineurin interaction.