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Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure.

ABSTRACT: Decreased activity and expression of the cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a), a critical pump regulating calcium cycling in cardiomyocyte, are hallmarks of heart failure. We have previously described a role for the small ubiquitin-like modifier type 1 (SUMO-1) as a regulator of SERCA2a and have shown that gene transfer of SUMO-1 in rodents and large animal models of heart failure restores cardiac function. Here, we identify and characterize a small molecule, N106, which increases SUMOylation of SERCA2a. This compound directly activates the SUMO-activating enzyme, E1 ligase, and triggers intrinsic SUMOylation of SERCA2a. We identify a pocket on SUMO E1 likely to be responsible for N106's effect. N106 treatment increases contractile properties of cultured rat cardiomyocytes and significantly improves ventricular function in mice with heart failure. This first-in-class small-molecule activator targeting SERCA2a SUMOylation may serve as a potential therapeutic strategy for treatment of heart failure.

SUBMITTER: Kho C

PROVIDER: S-EPMC4467461 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Qifu Yixin Formula Improves Heart Failure by Enhancing β-Arrestin2 Mediated the SUMOylation of SERCA2a.

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Small-Molecule-Induced ERBB4 Activation to Treat Heart Failure

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2024-11-13 | GSE261219 | GEO

Small-Molecule-Induced ERBB4 Activation to Treat Heart Failure

Project description:To determine the transcriptomic changes of small-molecule-induced activation of ERBB4 in heart failure, we tested the effects of the two small molecules (NRG1 and EF-1) of ERBB4 agonists on iAM (immortalized atrial cardiomyocytes) model. The transcriptional profiles of mRNA in these samples will be measured with high throughput technology. Changes in transcriptional profiles between the activation of EF-1 and NRG1 will be compared.

2024-11-13 | GSE256024 | GEO

Small-Molecule-Induced ERBB4 Activation to Treat Heart Failure

Project description:Small-Molecule-Induced ERBB4 Activation to Treat Heart Failure

| PRJNA1077406 | ENA

Small-Molecule-Induced ERBB4 Activation to Treat Heart Failure

Project description:Small-Molecule-Induced ERBB4 Activation to Treat Heart Failure

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SUMO1-dependent modulation of SERCA2a in heart failure.

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Selective SERCA2a activator as a candidate for chronic heart failure therapy.

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| S-EPMC10797746 | biostudies-literature

Correcting Calcium Dysregulation in Chronic Heart Failure Using SERCA2a Gene Therapy.

Project description:Chronic heart failure (CHF) is a major contributor to cardiovascular disease and is the leading cause of hospitalization for those over the age of 65, which is estimated to account for close to seventy billion dollars in healthcare costs by 2030 in the US alone. The successful therapies for preventing and reversing CHF progression are urgently required. One strategy under active investigation is to restore dysregulated myocardial calcium (Ca2+), a hallmark of CHF. It is well established that intracellular Ca2+ concentrations are tightly regulated to control efficient myocardial systolic contraction and diastolic relaxation. Among the many cell surface proteins and intracellular organelles that act as the warp and woof of the regulatory network controlling intracellular Ca2+ signals in cardiomyocytes, sarco/endoplasmic reticulum Ca2+ ATPase type 2a (SERCA2a) undoubtedly plays a central role. SERCA2a is responsible for sequestrating cytosolic Ca2+ back into the sarcoplasmic reticulum during diastole, allowing for efficient uncoupling of actin-myosin and subsequent ventricular relaxation. Accumulating evidence has demonstrated that the expression of SERCA2a is downregulated in CHF, which subsequently contributes to severe systolic and diastolic dysfunction. Therefore, restoring SERCA2a expression and improving cardiomyocyte Ca2+ handling provides an excellent alternative to currently used transplantation and mechanical assist devices in the treatment of CHF. Indeed, advancements in safe and effective gene delivery techniques have led to the emergence of SERCA2a gene therapy as a potential therapeutic choice for CHF patients. This mini-review will succinctly detail the progression of SERCA2a gene therapy from its inception in plasmid and animal models, to its clinical trials in CHF patients, highlighting potential avenues for future work along the way.

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Project description:The loss of dystrophin or its associated proteins results in the development of muscle wasting frequently associated with cardiomyopathy. Contractile cardiac tissue is injured and replaced by fibrous tissue or fatty infiltrates, leading to a progressive decrease of the contractile force and finally to end-stage heart failure. At the time symptoms appear, restoration of a functional allele of the causative gene might not be sufficient to prevent disease progression. Alterations in Ca(2+) transport and intracellular calcium levels have been implicated in many types of pathological processes, especially in heart disease. On the basis of a gene transfer strategy, we analyzed the therapeutic efficacy of primary gene correction in a ?-sarcoglycan (?-SG)-deficient animal model versus gene transfer of the Ca(2+) pump hSERCA2a (human sarco-endoplasmic reticulum calcium ATPase 2a), at a symptomatic stage of heart disease. Our results strongly suggest that restoration of ?-SG at this stage of disease will not lead to improved clinical outcome. However, restoration of proper Ca(2+) handling by means of amplifying SERCA2a expression in the myocardium can lead to functional improvement. Abnormalities in Ca(2+) handling play an important role in disease progression toward heart failure, and increased SERCA2a levels appear to significantly improve cardiac contraction and relaxation. Beneficial effects persist at least over a period of 6 months, and the evolution of cardiac functional parameters paralleled those of normal controls. Furthermore, we demonstrate that a plasmid formulation based on amphiphilic block copolymers can provide a safe and efficient platform for myocardial gene therapies. The use of synthetic formulations for myocardial gene transfer might thus overcome one of the major hurdles linked to viral vectors, that is, repeat administrations.

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Toll-Like Receptor 9 Promotes Survival in SERCA2a KO Heart Failure Mice.

Project description:Aim. Inflammation is important in heart failure (HF). The role of the immune receptor toll-like receptor 9 (TLR9) in HF is not understood and not investigated in diastolic HF. We investigated the role of TLR9 in a murine diastolic HF model caused by cardiomyocyte SERCA2a excision. Methods and Results. We crossed SERCA2a KO and TLR9 KO mice to generate four mouse lines. Tamoxifen-induced cardiomyocyte SERCA2a gene excision was carried out in mice, causing diastolic HF. After 7.6 weeks, cardiac functions and dimensions were analyzed by echocardiography and heart tissues were processed. HF mice depleted of TLR9 demonstrated reduced survival compared to SERC2a KO mice, with a median life expectancy of 58 days compared to 63 days. Both HF groups displayed increased left atrium size, lung weight, fetal gene expressions, monocyte/macrophage infiltration, and fibrosis. However, there were no significant differences between the groups. Conclusion. In mice with SERCA2a KO-induced diastolic HF, the absence of TLR9 reduced median life expectancy. The cause remains elusive, as all investigated HF parameters were unaltered. Still, these findings support a salutary role of TLR9 in some subsets of HF conditions and underline the importance for future studies on the mechanisms of TLR9 in diastolic HF.

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