bims-hafaim 2021-04-04 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021–04–04
eleven papers selected by
Kyle McCommis, Saint Louis University

Identification of Lactate as a Cardiac Protectant by Inhibiting Inflammation and Cardiac Hypertrophy Using a Zebrafish Acute Heart Failure Model.
Seipin Deficiency Accelerates Heart Failure Due to Calcium Handling Abnormalities and Endoplasmic Reticulum Stress in Mice.
Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction: A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial.
VEGF-C/VEGFR-3 axis protects against pressure-overload induced cardiac dysfunction through regulation of lymphangiogenesis.
Metabolic Interventions to Prevent Hypertrophy-Induced Alterations in Contractile Properties In Vitro.
Cardioprotective effects of severe calorie restriction from birth in adult ovariectomized rats.
Bcl-2 Is Involved in Cardiac Hypertrophy through PI3K-Akt Pathway.
Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 through epigenetic modification.
Proteomics study on the effect of silybin on cardiomyopathy in obese mice.
Upregulated Angiogenesis Is Incompetent to Rescue Dilated Cardiomyopathy Phenotype in Mice.
SERCA2a stimulation by istaroxime improves intracellular Ca2+ handling and diastolic dysfunction in a model of diabetic cardiomyopathy.

Pharmaceuticals (Basel). 2021 Mar 15. pii: 261. [Epub ahead of print]14(3):

Identification of Lactate as a Cardiac Protectant by Inhibiting Inflammation and Cardiac Hypertrophy Using a Zebrafish Acute Heart Failure Model.

Elijah R Haege, Hui-Chi Huang, Cheng-Chen Huang.

  Acute heart failure (AHF) commonly arises from decompensated chronic heart failure or sudden structural and functional breakdown causing a decrease in cardiac contractility and consequently fluid accumulation and systemic congestion. Current treatment for AHF aims at reducing fluid overload and improving hemodynamic which results in quick symptom relief but still poor prognostic outcome. This study utilizes a zebrafish AHF model induced by aristolochic acid (AA) to look for natural products that could attenuate the progression of AHF. The project started off by testing nearly seventy herbal crude extracts. Two of the positive extracts were from Chinese water chestnuts and are further studied in this report. After several rounds of chromatographical chemical fractionation and biological tests, a near pure fraction, named A2-4-2-4, with several hydrophilic compounds was found to attenuate the AA-induced AHF. A2-4-2-4 appeared to inhibit inflammation and cardiac hypertrophy by reducing MAPK signaling activity. Chemical analyses revealed that the major compound in A2-4-2-4 is actually lactate. Pure sodium lactate showed attenuation of the AA-induced AHF and inflammation and cardiac hypertrophy suppression as well, suggesting that the AHF attenuation ability in A2-4-2-4 is attributable to lactate. Our studies identify lactate as a cardiac protectant and a new therapeutic agent for AHF.

Keywords:  acute heart failure; cardiac hypertrophy; inflammation; lactate; zebrafish

DOI:  https://doi.org/10.3390/ph14030261
Front Cardiovasc Med. 2021 ;8 644128

Seipin Deficiency Accelerates Heart Failure Due to Calcium Handling Abnormalities and Endoplasmic Reticulum Stress in Mice.

Xiaoyue Wu, Xuejing Liu, Huan Wang, Zihao Zhou, Chengzhi Yang, Zijian Li, Youyi Zhang, XiaoLu Shi, Ling Zhang, Yuhui Wang, Xunde Xian, George Liu, Wei Huang.

  Seipin deficiency can induce hypertrophic cardiomyopathy and heart failure, which often leads to death in humans. To explore the effects and the possible mechanisms of Seipin deficiency in myocardial remodeling, Seipin knockout (SKO) mice underwent transverse aortic constriction (TAC) for 12 weeks. We found a more severe left ventricular hypertrophy and diastolic heart failure and increases in inflammatory cell infiltration, collagen deposition, and apoptotic bodies in the SKO group compared to those in the wild type (WT) group after TAC. Electron microscopy also showed a more extensive sarcoplasmic reticulum expansion, deformation of microtubules, and formation of mitochondrial lesions in the cardiomyocytes of SKO mice than in those of WT mice after TAC. Compared with the WT group, the SKO group showed increases in endoplasmic reticulum (ER) stress-, inflammation-, and fibrosis-related gene expression, while calcium ion-related factors, such as Serca2a and Ryr, were decreased in the SKO group after TAC. Increased levels of the ER stress-related protein GRP78 and decreased SERCA2a and P-RYR protein levels were detected in the SKO group compared with the WT group after TAC. Slowing of transient Ca2+ current decay and an increased SR Ca2+ content in myocytes were detected in the cardiomyocytes of SKO mice. Adipose tissue transplantation could not rescue the cardiac hypertrophy after TAC in SKO mice. In conclusion, we found that Seipin deficiency could promote cardiac hypertrophy and diastolic heart failure after TAC in mice. These changes may be related to the impairment of myocardial calcium handling, ER stress, inflammation, and apoptosis.

Keywords:  SERCA2a; calcium handling; diastolic heart failure; endoplasmic reticulum stress; seipin

DOI:  https://doi.org/10.3389/fcvm.2021.644128
JAMA Cardiol. 2021 Mar 31.

Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction: A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial.

Jawad H Butt, Kieran F Docherty, Mark C Petrie, Morten Schou, Mikhail N Kosiborod, Eileen O'Meara, Tzvetana Katova, Charlotta E A Ljungman, Mirta Diez, Modele O Ogunniyi, Anna Maria Langkilde, Mikaela Sjöstrand, Daniel Lindholm, Olof Bengtsson, Felipe A Martinez, Piotr Ponikowski, Marc S Sabatine, Scott D Solomon, Pardeep S Jhund, John J V McMurray, Lars Køber.

Importance: Women may respond differently to certain treatments for heart failure (HF) with reduced ejection fraction (HFrEF) than men.
Objective: To investigate the efficacy and safety of dapagliflozin compared with placebo in men and women with HFrEF enrolled in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).
Design, Setting, and Participants: Prespecified subgroup analysis of a phase 3 randomized clinical trial conducted at 410 sites in 20 countries. Patients with New York Heart Association functional class II through IV with an ejection fraction of 40% or less and elevated N-terminal pro-B-type natriuretic peptide were eligible. Data were analyzed between June 2020 and January 2021.
Interventions: Addition of once-daily 10 mg of dapagliflozin or placebo to guideline-recommended therapy.
Main Outcomes and Measures: The primary outcome was the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or cardiovascular death.
Results: A total of 4744 patients were randomized in DAPA-HF, of whom 1109 were women (23.4%). Compared with placebo, dapagliflozin reduced the risk of worsening HF events or cardiovascular death to a similar extent in both men and women (hazard ratios, 0.73 [95% CI, 0.63-0.85] and 0.79 [95% CI, 0.59-1.06], respectively; P for interaction = .67). Consistent benefits were observed for the components of the primary outcome and all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement in symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score of ≥5 points; men, 59% vs 50%; women, 57% vs 54%; P for interaction = .14) and decreased the proportion with worsening symptoms (Kansas City Cardiomyopathy Questionnaire total symptom score decrease of ≥5 points; men, 25% vs 34%; women, 27% vs 31%; P for interaction = .15), irrespective of sex. Results were consistent for the Kansas City Cardiomyopathy Questionnaire clinical summary score and overall summary score. Study drug discontinuation and serious adverse events were not more frequent in the dapagliflozin group than in the placebo group in either men or women.
Conclusions and Relevance: Dapagliflozin reduced the risk of worsening HF, cardiovascular death, and all-cause death and improved symptoms, physical function, and health-related quality of life similarly in men and women with heart failure and reduced ejection fraction. In addition, dapagliflozin was safe and well-tolerated irrespective of sex.
Trial Registration: ClinicalTrials.gov Identifier: NCT03036124.

DOI: https://doi.org/10.1001/jamacardio.2021.0379
Clin Transl Med. 2021 Mar;11(3): e374

VEGF-C/VEGFR-3 axis protects against pressure-overload induced cardiac dysfunction through regulation of lymphangiogenesis.

Qiu-Yue Lin, Yun-Long Zhang, Jie Bai, Jin-Qiu Liu, Hui-Hua Li.

  Prolonged pressure overload triggers cardiac hypertrophy and frequently leads to heart failure (HF). Vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 are components of the central pathway for lymphatic vessel growth (also known as lymphangiogenesis), which has crucial functions in the maintenance of tissue fluid balance and myocardial function after ischemic injury. However, the roles of this pathway in the development of cardiac hypertrophy and dysfunction during pressure overload remain largely unknown. Eight- to 10-week-old male wild-type (WT) mice, VEGFR-3 knockdown (VEGFR-3f/- ) mice, and their WT littermates (VEGFR-3f/f ) were subjected to pressure overload induced by transverse aortic constriction (TAC) for 1-6 weeks. We found that cardiac lymphangiogenesis and the protein expression of VEGF-C and VEGFR-3 were upregulated in the early stage of cardiac hypertrophy but were markedly reduced in failing hearts. Moreover, TAC for 6 weeks significantly reduced cardiac lymphangiogenesis by inhibiting activation of VEGFR-3-mediated signals (AKT/ERK1/2, calcineurin A/NFATc1/FOXc2, and CX43), leading to increased cardiac edema, hypertrophy, fibrosis, apoptosis, inflammation, and dysfunction. These effects were further aggravated in VEGFR-3f/- mice and were dose-dependently attenuated by delivery of recombinant VEGF-C156S in WT mice. VEGF-C156s administration also reversed pre-established cardiac dysfunction induced by sustained pressure overload. Thus, these results demonstrate, for the first time, that activation of the VEGF-C-VEGFR-3 axis exerts a protective effect during the transition from cardiac hypertrophy to HF and highlight selective stimulation of cardiac lymphangiogenesis as a potential new therapeutic approach for hypertrophic heart diseases.

Keywords:  VEGF-C; VEGFR-3; cardiac lymphangiogenesis; heart failure; pressure overload

DOI:  https://doi.org/10.1002/ctm2.374
Int J Mol Sci. 2021 Mar 31. pii: 3620. [Epub ahead of print]22(7):

Metabolic Interventions to Prevent Hypertrophy-Induced Alterations in Contractile Properties In Vitro.

Ilvy M E Geraets, Will A Coumans, Agnieszka Strzelecka, Patrick Schönleitner, Gudrun Antoons, Francesco Schianchi, Myrthe M A Willemars, Dimitrios Kapsokalyvas, Jan F C Glatz, Joost J F P Luiken, Miranda Nabben.

  (1) Background: The exact mechanism(s) underlying pathological changes in a heart in transition to hypertrophy and failure are not yet fully understood. However, alterations in cardiac energy metabolism seem to be an important contributor. We characterized an in vitro model of adrenergic stimulation-induced cardiac hypertrophy for studying metabolic, structural, and functional changes over time. Accordingly, we investigated whether metabolic interventions prevent cardiac structural and functional changes; (2) Methods: Primary rat cardiomyocytes were treated with phenylephrine (PE) for 16 h, 24 h, or 48 h, whereafter hypertrophic marker expression, protein synthesis rate, glucose uptake, and contractile function were assessed; (3) Results: 24 h PE treatment increased expression of hypertrophic markers, phosphorylation of hypertrophy-related signaling kinases, protein synthesis, and glucose uptake. Importantly, the increased glucose uptake preceded structural and functional changes, suggesting a causal role for metabolism in the onset of PE-induced hypertrophy. Indeed, PE treatment in the presence of a PAN-Akt inhibitor or of a GLUT4 inhibitor dipyridamole prevented PE-induced increases in cellular glucose uptake and ameliorated PE-induced contractile alterations; (4) Conclusions: Pharmacological interventions, forcing substrate metabolism away from glucose utilization, improved contractile properties in PE-treated cardiomyocytes, suggesting that targeting glucose uptake, independent from protein synthesis, forms a promising strategy to prevent hypertrophy and hypertrophy-induced cardiac dysfunction.

Keywords:  adult rat cardiomyocytes; cardiac hypertrophy; glucose uptake; metabolic modulation; phenylephrine

DOI:  https://doi.org/10.3390/ijms22073620
Life Sci. 2021 Mar 24. pii: S0024-3205(21)00396-9. [Epub ahead of print]275 119411

Cardioprotective effects of severe calorie restriction from birth in adult ovariectomized rats.

Cíntia Maria Rodrigues, Talita Emanuela Domingues, Carina de Sousa Santos, Liliane Vanessa Costa-Pereira, Bruno Ferreira Mendes, Jousielle Márcia Dos Santos, Karine Beatriz Costa, Gabriela Silva, Vinícius Lopes Cantuária, Etel Rocha-Vieira, Marco Fabrício Dias-Peixoto, Kinulpe Honorato-Sampaio.

   AIMS: Menopause is a female condition induced by a reduction of ovarian hormone and is related to an increase in cardiovascular diseases in women. We have shown that severe calorie restriction (SCR) from birth reduces the cardiometabolic risk in adult male Wistar rats. In this study, we investigated the effects of SCR from birth to adulthood on cardiovascular function of ovariectomized rats.
MAIN METHODS: From birth to adulthood, rats were daily fed ad libitum (control group - C) or with 50% of the amount consumed by the control group (calorie-restricted group - R). At 90 days, half of the rats in each group underwent bilateral ovariectomy (OVX), totaling 4 groups: C-Sham, C-OVX, R-Sham, R-OVX. Systolic blood pressure (SBP), heart rate (HR) and, double product (DP) index were recorded by tail-cuff plethysmography. Cardiac function was analyzed by the Langendorff technique and cardiomyocyte diameter was accessed by histologic analysis. Additionally, cardiac SERCA2 content and redox status were evaluated.
KEY FINDINGS: C-OVX rats exhibited reduced cardiac function and cardiac non-enzymatic total antioxidant capacity (TAC). R-Sham animals showed reduced SBP, DP, HR, improved cardiac function, reduced cardiac protein carbonyl derivatives and increased TAC, catalase, and superoxide dismutase activities. R-OVX rats maintained reduced SBP, DP, HR, and increased contractility and relaxation indexes. R-Sham and R-OVX rats exhibited preserved heart mass and reduced cardiomyocyte diameter. Cardiac SERCA2 content did not differ between the groups.
SIGNIFICANCE: Taken together, our findings show cardioprotective effects of SCR from birth in adult ovariectomized rats.

Keywords:  Calorie restriction; Heart function; Menopause; Ovariectomy; Redox status

DOI:  https://doi.org/10.1016/j.lfs.2021.119411
Biomed Res Int. 2021 ;2021 6615502

Bcl-2 Is Involved in Cardiac Hypertrophy through PI3K-Akt Pathway.

Xianwei Meng, Jun Cui, Guibin He.

Cardiac hypertrophy (CH) is a common cause of sudden cardiac death and heart failure, resulting in a significant medical burden. The present study is aimed at exploring potential CH-related pathways and the key downstream effectors. The gene expression profile of GSE129090 was obtained from the Gene Expression Omnibus database (GEO), and 1325 differentially expressed genes (DEGs) were identified, including 785 upregulated genes and 540 downregulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway enrichment analysis of DEGs were then performed. Although there were no pathways enriched by downregulated genes, many CH-related pathways were identified by upregulated genes, including PI3K-Akt signaling pathway, extracellular matrix- (ECM-) receptor interaction, regulation of actin cytoskeleton, and hypertrophic cardiomyopathy (HCM). In the deeper analysis of PI3K-Akt signaling pathway, we found all the signaling transduction pointed to B cell lymphoma-2- (Bcl-2-) mediated cell survival. We then demonstrated that PI3K-Akt signaling pathway was indeed activated in cardiac hypertrophy. Furthermore, no matter LY294002, an inhibitor of the PI3K/AKT signaling pathway, or Venetoclax, a selective Bcl-2 inhibitor, protected against cardiac hypertrophy. In conclusion, these data indicate that Bcl-2 is involved in cardiac hypertrophy as a key downstream effector of PI3K-Akt signaling pathway, suggesting a potential therapeutic target for the clinical management of cardiac hypertrophy.

DOI: https://doi.org/10.1155/2021/6615502
J Cell Mol Med. 2021 Apr 01.

Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 through epigenetic modification.

Xuling Su, Shudong Wang, Haiying Zhang, Ge Yang, Yang Bai, Pinyi Liu, Lingbin Meng, Xin Jiang, Ying Xin.

  Nuclear factor erythroid 2-related factor (Nrf2) is an important regulator of cellular antioxidant defence. We previously showed that SFN prevented Ang II-induced cardiac damage via activation of Nrf2. However, the underlying mechanism of SFN's persistent cardiac protection remains unclear. This study aimed to explore the potential of SFN in activating cardiac Nrf2 through epigenetic mechanisms. Wild-type mice were injected subcutaneously with Ang II, with or without SFN. Administration of chronic Ang II-induced cardiac inflammatory factor expression, oxidative damage, fibrosis and cardiac remodelling and dysfunction, all of which were effectively improved by SFN treatment, coupled with an up-regulation of Nrf2 and downstream genes. Bisulfite genome sequencing and chromatin immunoprecipitation (ChIP) were performed to detect the methylation level of the first 15 CpGs and histone H3 acetylation (Ac-H3) status in the Nrf2 promoter region, respectively. The results showed that SFN reduced Ang II-induced CpG hypermethylation and promoted Ac-H3 accumulation in the Nrf2 promoter region, accompanied by the inhibition of global DNMT and HDAC activity, and a decreased protein expression of key DNMT and HDAC enzymes. Taken together, SFN exerts its cardioprotective effect through epigenetic modification of Nrf2, which may partially contribute to long-term activation of cardiac Nrf2.

Keywords:  angiotensin II; epigenetics; nuclear factor E2 related factor 2; oxidative stress; sulforaphane

DOI:  https://doi.org/10.1111/jcmm.16504
Sci Rep. 2021 Mar 30. 11(1): 7136

Proteomics study on the effect of silybin on cardiomyopathy in obese mice.

Fei Wang, Zelin Li, Tiantian Song, Yujiao Jia, Licui Qi, Luping Ren, Shuchun Chen.

Due to the increase in the number of obese individuals, the incidence of obesity-related complications such as cardiovascular disease and type 2 diabetes is higher. The aim of the present study was to explore the effects of silybin on protein expression in obese mice. Firstly, serum was collected, and it was used to detect serum lipids and other serological indicators. Secondly, total protein from epididymal adipose tissue was extracted for differential expression analysis by quantitative tandem mass tag (TMT) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), followed by bioinformatics and protein-protein interaction (PPI) network analyses of these proteins. Lastly, real-time polymerase chain reaction (RT-PCR) and parallel reaction monitoring (PRM) were used to further validate the expression of identified differentially expressed proteins (DEPs) at the mRNA and protein level, respectively. The results revealed that silybin could improve abnormal lipid metabolism caused by the high fat diet in obese mice. A total of 341, 538 and 243 DEPs were found in the high fat/control (WF/WC), silybin/high fat (WS/WF) and WS/WC groups, respectively. These DEPs mainly participated in lipid metabolism and energy metabolism. Notably, tropomyosin 1 (TPM1), myosin light chain 2 (MYL2), myosin heavy chain 11 (MYH11) and other DEPs were involved in hypertrophic cardiomyopathy, dilated cardiomyopathy and other pathways. Silybin could protect cardiac function by inducing the protein expression of TPM1, MYL2 and MYH11 in the adipose tissue of obese mice.

DOI: https://doi.org/10.1038/s41598-021-86717-x
Cells. 2021 Mar 31. pii: 771. [Epub ahead of print]10(4):

Upregulated Angiogenesis Is Incompetent to Rescue Dilated Cardiomyopathy Phenotype in Mice.

Mohammed Arif, Perwez Alam, Rafeeq Ph Ahmed, Raghav Pandey, Hafeez M Faridi, Sakthivel Sadayappan.

  Dilated cardiomyopathy (DCM) is characterized by pathologic cardiac remodeling resulting in chambers enlargement and impaired heart contractility. Previous reports and our in-silico analysis support the association of DCM phenotype and impaired tissue angiogenesis. Here, we explored whether the modulation in cardiac angiogenesis partly intervenes or rescues the DCM phenotype in mice. Here, a DCM mouse model [α-tropomyosin 54 (α-TM54) mutant] was crossbred with microRNA-210 transgenic mice (210-TG) to develop microRNA-210 (miR-210) overexpressing α-TM54 mutant mice (TMx210). Contrary to wild-type (WT) and 210-TG mice, a significant increase in heart weight to body weight ratio in aged mixed-gender TMx210 and DCM mice was recorded. Histopathological analysis revealed signs of pathological cardiac remodeling such as myocardial disarray, myofibrillar loss, and interstitial fibrosis in DCM and TMx210 mice. Contrary to WT and DCM, a significant increase in angiogenic potential was observed in TMx210 and 210-TG mice hearts which is reflected by higher blood vessel density and upregulated proangiogenic vascular endothelial growth factor-A. The echocardiographic assessment showed comparable cardiac dysfunction in DCM and TMx210 mice as compared to WT and 210-TG. Overall, the present study concludes that miR-210 mediated upregulated angiogenesis is not sufficient to rescue the DCM phenotype in mice.

Keywords:  MicroRNA-210; angiogenesis; dilated cardiomyopathy

DOI:  https://doi.org/10.3390/cells10040771
Cardiovasc Res. 2021 Apr 01. pii: cvab123. [Epub ahead of print]

SERCA2a stimulation by istaroxime improves intracellular Ca2+ handling and diastolic dysfunction in a model of diabetic cardiomyopathy.

Eleonora Torre, Martina Arici, Alessandra Maria Lodrini, Mara Ferrandi, Paolo Barassi, Shih-Che Hsu, Gwo-Jyh Chang, Elisabetta Boz, Emanuela Sala, Sara Vagni, Claudia Altomare, Gaspare Mostacciuolo, Claudio Bussadori, Patrizia Ferrari, Giuseppe Bianchi, Marcella Rocchetti.

AIMS: Diabetic 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 RESULTS: Streptozotocin (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 1) marked DD not associated to cardiac fibrosis, 2) LV mass reduction associated to reduced LV cell dimension and T-tubules loss, 3) reduced LV SERCA2 protein level and activity and 4) slower SR Ca2+ uptake rate, 5) LV action potential (AP) prolongation and increased short-term variability (STV) of AP duration, 6) increased diastolic Ca2+, and 7) 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.
CONCLUSIONS: SERCA2a 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.
TRANSLATIONAL PERSPECTIVE: Deficient sarcoplasmic reticulum (SR) Ca2+ uptake has been identified in cardiomyocytes from failing human hearts with impaired diastolic relaxation (e.g. diabetic hearts) and has been associated with a decreased SERCA2a expression and activity and/or with a higher SERCA2a inhibition by phospholamban. Thus, SERCA2a may represent a pharmacological target for interventions aimed at improving cytosolic Ca2+ compartmentalization into the SR to limit diastolic dysfunction pathologies. In this context, istaroxime is the first-in-class luso-inotropic agent targeting SERCA2a that has already demonstrated its efficacy in clinical trials and may be useful to clarify the relevance of SERCA2a stimulation in controlling cytosolic Ca2+ level.

DOI: https://doi.org/10.1093/cvr/cvab123