Vafiadaki E, Arvanitis DA, Eliopoulos AG, Kranias EG, Sanoudou D
. The Cardioprotective PKA-Mediated Hsp20 Phosphorylation Modulates Protein Associations Regulating Cytoskeletal Dynamics
. Int J Mol SciInt J Mol SciInt J Mol Sci. 2020;21.Abstract
The cytoskeleton has a primary role in cardiomyocyte function, including the response to mechanical stimuli and injury. The small heat shock protein 20 (Hsp20) conveys protective effects in cardiac muscle that are linked to serine-16 (Ser16) Hsp20 phosphorylation by stress-induced PKA, but the link between Hsp20 and the cytoskeleton remains poorly understood. Herein, we demonstrate a physical and functional interaction of Hsp20 with the cytoskeletal protein 14-3-3. We show that, upon phosphorylation at Ser16, Hsp20 translocates from the cytosol to the cytoskeleton where it binds to 14-3-3. This leads to dissociation of 14-3-3 from the F-actin depolymerization regulator cofilin-2 (CFL2) and enhanced F-actin depolymerization. Importantly, we demonstrate that the P20L Hsp20 mutation associated with dilated cardiomyopathy exhibits reduced physical interaction with 14-3-3 due to diminished Ser16 phosphorylation, with subsequent failure to translocate to the cytoskeleton and inability to disassemble the 14-3-3/CFL2 complex. The topological sequestration of Hsp20 P20L ultimately results in impaired regulation of F-actin dynamics, an effect implicated in loss of cytoskeletal integrity and amelioration of the cardioprotective functions of Hsp20. These findings underscore the significance of Hsp20 phosphorylation in the regulation of actin cytoskeleton dynamics, with important implications in cardiac muscle physiology and pathophysiology.
Sorce S, Nuvolone M, Russo G, Chincisan A, Heinzer D, Avar M, Pfammatter M, Schwarz P, Delic M, Muller M, et al. Genome-wide transcriptomics identifies an early preclinical signature of prion infection
. PLoS PathogPLoS PathogPLoS Pathog. 2020;16:e1008653.Abstract
The clinical course of prion diseases is accurately predictable despite long latency periods, suggesting that prion pathogenesis is driven by precisely timed molecular events. We constructed a searchable genome-wide atlas of mRNA abundance and splicing alterations during the course of disease in prion-inoculated mice. Prion infection induced PrP-dependent transient changes in mRNA abundance and processing already at eight weeks post inoculation, well ahead of any neuropathological and clinical signs. In contrast, microglia-enriched genes displayed an increase simultaneous with the appearance of clinical signs, whereas neuronal-enriched transcripts remained unchanged until the very terminal stage of disease. This suggests that glial pathophysiology, rather than neuronal demise, could be the final driver of disease. The administration of young plasma attenuated the occurrence of early mRNA abundance alterations and delayed signs in the terminal phase of the disease. The early onset of prion-induced molecular changes might thus point to novel biomarkers and potential interventional targets.
Gkouskou KK, Grammatikopoulou MG, Vlastos I, Sanoudou D, Eliopoulos AG
. Genotype-guided dietary supplementation in precision nutrition
. Nutr RevNutr RevNutr Rev. 2020.Abstract
Achieving adequate micronutrient status, while avoiding deficiencies, represents a challenge for people globally. Consequently, many individuals resort to oral nutrient supplementation (ONS) in order to correct suboptimal dietary intakes. Advances in the fields of nutrigenetics and nutritional genomics have identified differences in response to micronutrient supplementation according to genetic makeup, adding dietary supplement use to the clinician's toolkit in the precision nutrition era. This review focuses on published evidence linking genetic variants to the responses associated with some of the most popular dietary supplements. With an increasing number of health professionals becoming involved in the prescription of ONS, identifying and matching individuals to the appropriate dietary supplement according to their genotype is important for achieving optimal health benefits and micronutrient equilibrium, while reducing the adverse events and financial costs often associated with excessive ONS.
Gkouskou K, Vlastos I, Karkalousos P, Chaniotis D, Sanoudou D, Eliopoulos AG
. The "Virtual Digital Twins" Concept in Precision Nutrition
. Adv NutrAdv NutrAdv Nutr. 2020;11:1405-1413.Abstract
Nutritional and lifestyle changes remain at the core of healthy aging and disease prevention. Accumulating evidence underscores the impact of genetic, metabolic, and host gut microbial factors on individual responses to nutrients, paving the way for the stratification of nutritional guidelines. However, technological advances that incorporate biological, nutritional, lifestyle, and health data at an unprecedented scale and depth conceptualize a future where preventative dietary interventions will exceed stratification and will be highly individualized. We herein discuss how genetic information combined with longitudinal metabolomic, immune, behavioral, and gut microbial parameters, and bioclinical variables could define a digital replica of oneself, a "virtual digital twin," which could serve to guide nutrition in a personalized manner. Such a model may revolutionize the management of obesity and its comorbidities, and provide a pillar for healthy aging.
Efentakis P, Varela A, Chavdoula E, Sigala F, Sanoudou D, Tenta R, Gioti K, Kostomitsopoulos N, Papapetropoulos A, Tasouli A, et al. Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy
. Cardiovasc ResCardiovasc ResCardiovasc Res. 2020;116:576-591.Abstract
AIMS: Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity. METHODS AND RESULTS: Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 mug/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 mug/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN-/-) mice were assigned to PLN-/-/Control (N/S-0.9%), PLN-/-/DXR (18 mg/kg), and PLN-/-/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 mug/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan's cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN-/- mice. Levosimendan's cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload. CONCLUSION: Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.