ArticleCardiovascular research2022
SERCA2a stimulation by istaroxime improves intracellular Ca2+ handling and diastolic dysfunction in a model of diabetic cardiomyopathy.
Article in Cardiovascular research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 50 citations in OpenAlex.
- KCNE2 upregulation improves cardiac function by inhibiting Smurf1-mediated SERCA2a degradation in diabetic cardiomyopathy in mice.Acta pharmacologica Sinica · 2026Article
- Istaroxime in Acute Heart Failure and Early Cardiogenic Shock: A Calcium-Cycling Approach to Inotropic Therapy.International journal of molecular sciences · 2026Review
- The Landscape of SERCA2 in Cardiovascular Diseases: Expression Regulation, Therapeutic Applications, and Emerging Roles.Biomolecules · 2026Review
- Cardiomyocyte-Specific RNF128 Attenuates Pathological Cardiac Hypertrophy Progression by Stabilizing SERCA2a through Lys63-Linked Polyubiquitination.Theranostics · 2026Article
- Astragaloside IV prevents calpain-1-mediated cardiac hypertrophy and fibrosis induced by diabetes.Frontiers in cardiovascular medicine · 2026Article
- Small-Molecule Sarco/Endoplasmic Reticulum CaChemMedChem · 2026Article
- The SERCA-PLN-DWORF axis in cardiometabolic disease: mechanisms and therapeutic perspectives.Cardiovascular diabetology · 2025Review
- Article
- SERCA2a dysfunction in the pathophysiology of heart failure with preserved ejection fraction: a direct role is yet to be established.Heart failure reviews · 2025Review
- Novel Therapies for Right Ventricular Failure.Current cardiology reports · 2025Review
- MicroRNA: unveiling novel mechanistic and theranostic pathways in diabetic cardiomyopathy.Frontiers in pharmacology · 2025Review
- Far-infrared irradiation attenuates vessel contraction by activating SERCA2 through disruption of SERCA2 and PLN interaction.PloS one · 2025Article
- Mitochondrial dysfunction as a therapeutic nexus in HFpEF: therapeutic target and pharmacological advances.Frontiers in pharmacology · 2025Review
- Development of Small-molecule SERCA2a Stimulators: A Novel Class of Ino-lusitropic Agents.European cardiology · 2025Review
- NCardiovascular diabetology · 2024Article
- Diabetic Cardiomyopathy: Role of Cell Death, Exosomes, Fibrosis and Epicardial Adipose Tissue.International journal of molecular sciences · 2024Review
- Molecular Basis of Cardiomyopathies in Type 2 Diabetes.International journal of molecular sciences · 2024Review
- A Review of Contemporary and Future Pharmacotherapy for Chronic Heart Failure in Children.Children (Basel, Switzerland) · 2024Review
- Unraveling the Cardiac Matrix: From Diabetes to Heart Failure, Exploring Pathways and Potential Medications.Biomedicines · 2024Review
- Pathophysiology and Advances in the Therapy of Cardiomyopathy in Patients with Diabetes Mellitus.International journal of molecular sciences · 2024Review
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Authors and funding
16 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsDiabetic cardiomyopathy is a multifactorial disease characterized by an early onset of diastolic dysfunction (DD) that precedes the development of systolic impairment. Mechanisms that can restore cardiac relaxation improving intracellular Ca2+ dynamics represent a promising therapeutic approach for cardiovascular diseases associated to DD. Istaroxime has the dual properties to accelerate Ca2+ uptake into sarcoplasmic reticulum (SR) through the SR Ca2+ pump (SERCA2a) stimulation and to inhibit Na+/K+ ATPase (NKA). This project aims to characterize istaroxime effects at a concentration (100 nmol/L) marginally affecting NKA, in order to highlight its effects dependent on the stimulation of SERCA2a in an animal model of mild diabetes. METHODS AND
resultsStreptozotocin (STZ) treated diabetic rats were studied at 9 weeks after STZ injection in comparison to controls (CTR). Istaroxime effects were evaluated in vivo and in left ventricular (LV) preparations. STZ animals showed (i) marked DD not associated to cardiac fibrosis, (ii) LV mass reduction associated to reduced LV cell dimension and T-tubules loss, (iii) reduced LV SERCA2 protein level and activity and (iv) slower SR Ca2+ uptake rate, (v) LV action potential (AP) prolongation and increased short-term variability (STV) of AP duration, (vi) increased diastolic Ca2+, and (vii) unaltered SR Ca2+ content and stability in intact cells. Acute istaroxime infusion (0.11 mg/kg/min for 15 min) reduced DD in STZ rats. Accordingly, in STZ myocytes istaroxime (100 nmol/L) stimulated SERCA2a activity and blunted STZ-induced abnormalities in LV Ca2+ dynamics. In CTR myocytes, istaroxime increased diastolic Ca2+ level due to NKA blockade albeit minimal, while its effects on SERCA2a were almost absent.
conclusionsSERCA2a stimulation by istaroxime improved STZ-induced DD and intracellular Ca2+ handling anomalies. Thus, SERCA2a stimulation can be considered a promising therapeutic approach for DD treatment.
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