Related Experiment Video
Updated: May 29, 2026
11:00
Assessment of Sarcoplasmic Reticulum Calcium Reserve and Intracellular Diastolic Calcium Removal in Isolated Ventricular Cardiomyocytes
Published on: September 18, 2017
SUMO1-dependent modulation of SERCA2a in heart failure
Changwon Kho1, Ahyoung Lee, Dongtak Jeong
1Cardiovascular Research Center, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1030, New York, New York 10029, USA.
Nature
|September 9, 2011
Summary
SUMOylation of SERCA2a (sarco/endoplasmic reticulum calcium ATPase) is vital for heart function. Restoring SUMO1 levels improved cardiac function in heart failure models by stabilizing SERCA2a.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- The calcium-transporting ATPase ATP2A2 (SERCA2a) is crucial for cardiac excitation-contraction coupling.
- Reduced SERCA2a expression and activity are characteristic of heart failure.
- Gene therapy restoring SERCA2a improves cardiac function in heart failure.
Purpose of the Study:
- To investigate the role of small ubiquitin-related modifier (SUMO) conjugation in SERCA2a regulation.
- To determine if SUMOylation impacts SERCA2a activity, stability, and cardiac function.
- To explore SUMO1 as a potential therapeutic target for heart failure.
Main Methods:
- Identified SUMOylation sites on SERCA2a (lysines 480 and 585).
- Assessed SERCA2a SUMOylation levels in failing hearts.
- Utilized adeno-associated virus (AAV)-mediated gene delivery to restore SUMO1 in heart failure models.
- Employed small hairpin RNA (shRNA) to downregulate SUMO1.
- Evaluated cardiac function, contractility, and Ca(2+) handling in vitro and in vivo.
Main Results:
- SERCA2a SUMOylation at K480/K585 is essential for its ATPase activity and stability.
- SUMO1 levels and SERCA2a SUMOylation are decreased in failing hearts.
- AAV-mediated SUMO1 delivery improved cardiac function and SERCA2a abundance in mouse models of heart failure, comparable to SERCA2a gene delivery.
- SUMO1 overexpression enhanced cardiomyocyte contractility and Ca(2+) decay.
- SUMO1 downregulation exacerbated pressure-overload-induced cardiac dysfunction and decreased SERCA2a function.
Conclusions:
- SUMOylation is a critical post-translational modification regulating SERCA2a function and stability.
- Restoring SUMO1 levels offers a novel therapeutic strategy for heart failure by preserving SERCA2a function.
- Targeting SUMOylation pathways presents a promising avenue for developing new heart failure treatments.
Related Concept Videos
01:29Heart Failure II: Pathophysiology
Systolic Heart Failure and Compensatory MechanismsSystolic heart failure (also termed HFrEF, Heart Failure with Reduced Ejection Fraction) is the most prevalent type of heart filure. It results in a decreased volume of blood being pumped from the ventricle. The aortic arch and carotid sinuses have baroreceptors that detect reduced blood pressure, triggering the sympathetic nervous system (SNS) to release epinephrine and norepinephrine. Initially, this response aims to boost heart rate and...
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
The activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) contributes to cardiac remodeling, and inhibiting the RAAS is a pharmacological target in heart failure management. As a result, neurohumoral modulation is a crucial treatment principle for managing heart failure. This approach involves using medications like ACE inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers, mineralocorticoid receptor antagonists (MRAs), and neutral...
01:17Pathophysiology of Heart Failure
Heart failure (HF) is a progressive syndrome involving ventricles that leads to inadequate cardiac output. It can be classified based on location and output or ejection fraction. Ejection fraction (EF) is an essential measurement in the diagnosis and surveillance of HF. Reduced EF corresponds to systolic heart failure (HFrEF). However, HF with preserved ejection fraction (HFpEF) is becoming increasingly prevalent. Also known as diastolic HF, this form of HF is related to aging. The...
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy, or HCM, is an autosomal dominant genetic disorder characterized by asymmetric left ventricular hypertrophy without ventricular dilation. It is more common in men and is typically diagnosed in young, athletic adults.EtiologyHCM is primarily genetic and is caused by mutations in genes encoding sarcomeric proteins. Researchers have identified over 1400 mutations across at least 11 different genes. Among these, the most frequently occurring mutations are found in the...
01:30Heart Failure V: Medical Management
Medical Management of Acute Decompensated Heart Failure (ADHF)The primary goals of therapy for patients hospitalized with acute decompensated heart failure (ADHF) include:Relieving symptomsOptimizing volume statusSupporting oxygenation and ventilationMaintaining cardiac output (CO) and end-organ perfusionIdentifying and addressing the cause of ADHFPreventing complicationsProviding patient education on factors precipitating HF exacerbationPlanning for dischargeOngoing monitoring and assessment...
01:26Heart Failure Drugs: Inotropic Agents
Positive inotropic agents are commonly used as the first line of treatment for heart failure. One such agent is digoxin, derived from the genus Digitalis, which has been known for centuries but effectively utilized since 1785. However, these cardiac glycosides can have potentially toxic effects due to their mechanism of action, which involves inhibiting Na+/K+-ATPase and increasing contractility. Digoxin is absorbed orally and distributed in various tissues, including the CNS. It has a long...