The Oxidative Balance Orchestrates the Main Keystones of the Functional Activity of Cardiomyocytes

This review is aimed at providing an overview of the key hallmarks of cardiomyocytes in physiological and pathological conditions. The main feature of cardiac tissue is the force generation through contraction. This process requires a conspicuous energy demand and therefore an active metabolism. The cardiac tissue is rich of mitochondria, the powerhouses in cells. These organelles, producing ATP, are also the main sources of ROS whose altered handling can cause their accumulation and therefore triggers detrimental effects on mitochondria themselves and other cell components thus leading to apoptosis and cardiac diseases. This review highlights the metabolic aspects of cardiomyocytes and wanders through the main systems of these cells: (a) the unique structural organization (such as different protein complexes represented by contractile, regulatory, and structural proteins); (b) the homeostasis of intracellular Ca2+ that represents a crucial ion for cardiac functions and E-C coupling; and (c) the balance of Zn2+, an ion with a crucial impact on the cardiovascular system. Although each system seems to be independent and finely controlled, the contractile proteins, intracellular Ca2+ homeostasis, and intracellular Zn2+ signals are strongly linked to each other by the intracellular ROS management in a fascinating way to form a “functional tetrad” which ensures the proper functioning of the myocardium. Nevertheless, if ROS balance is not properly handled, one or more of these components could be altered resulting in deleterious effects leading to an unbalance of this “tetrad” and promoting cardiovascular diseases. In conclusion, this “functional tetrad” is proposed as a complex network that communicates continuously in the cardiomyocytes and can drive the switch from physiological to pathological conditions in the heart.

Popeye Domain-Containing Protein 1 Scaffolds a Complex of Adenylyl Cyclase 9 and the Two-Pore-Domain Potassium Channel TREK-1 in Heart

The establishment of macromolecular complexes by scaffolding proteins such as A-kinase anchoring proteins is key to the local production of cAMP by anchored adenylyl cyclase (AC) and the subsequent cAMP signaling necessary for many cardiac functions. We have identified herein a novel AC scaffold, the Popeye domain-containing (POPDC) protein. Unlike other AC scaffolding proteins, POPDC1 binds cAMP with high affinity. The POPDC family of proteins are important for cardiac pacemaking and conduction, due in part to their cAMP-dependent binding and regulation of TREK-1 potassium channels. TREK-1 binds the AC9:POPDC1 complex and co-purifies in a POPDC1-dependent manner with AC9-associated activity in heart. Although the interaction of AC9 and POPDC1 is cAMP independent, TREK-1 association with AC9 and POPDC1 is reduced in an isoproterenol-dependent manner, requiring an intact cAMP binding Popeye domain and AC activity within the complex. We show that deletion of Adcy9 (AC9) gives rise to bradycardia at rest and stress-induced heart rate variability. The phenotype for deletion of Adcy9 is milder than previously observed upon loss of Popdc1, but similar to loss of Kcnk2 (TREK-1). Thus, POPDC1 represents a novel scaffolding protein for AC9 to regulate heart rate control.

Physiological and Pathophysiological Roles of Mitochondrial Na+-Ca2+ Exchanger, NCLX, in Hearts

It has been over 10 years since SLC24A6/SLC8B1, coding the Na+/Ca2+/Li+ exchanger (NCLX), was identified as the gene responsible for mitochondrial Na+-Ca2+ exchange, a major Ca2+ efflux system in cardiac mitochondria. This molecular identification enabled us to determine structure–function relationships, as well as physiological/pathophysiological contributions, and our understandings have dramatically increased. In this review, we provide an overview of the recent achievements in relation to NCLX, focusing especially on its heart-specific characteristics, biophysical properties, and spatial distribution in cardiomyocytes, as well as in cardiac mitochondria. In addition, we discuss the roles of NCLX in cardiac functions under physiological and pathophysiological conditions—the generation of rhythmicity, the energy metabolism, the production of reactive oxygen species, and the opening of mitochondrial permeability transition pores.

CB2 receptor agonist and L- arginine combination attenuates diabetic cardiomyopathy in rats via NF-ĸβ inhibition

Beta-caryophyllene (BCP), a cannabinoid 2 receptor (CB2) agonist has recently been found to have cardioprotective activity as an anti-inflammatory and antioxidant molecule. L-arginine (LA), a nitric oxide (NO) donor is a potential regulator of cardiovascular function. Considering the role of CB2 receptor activation and NO regulation in cardiovascular diseases, the combination of BCP with LA may be a possible treatment of diabetic cardiomyopathy (DCM). Hence, we investigated the efficacy of the novel combination of BCP with LA on cardiovascular inflammation and oxidative stress in diabetic rats. DCM was induced by Streptozotocin (55 mg/kg) in SD rats intraperitoneally. BCP, LA and BCP with LA were administered to diabetic rats for 4 weeks. After completion of the study, hemodynamic parameters, biochemical parameters, and inflammatory cytokine levels were analyzed. Also, oxidative stress parameters, NF-ĸβ expression and histopathology in cardiac tissues were estimated. The combination of BCP (200 mg/kg) with LA (200 mg/kg) significantly normalized the hemodynamic parameters and decreased the glucose, cardiac markers, IL-6 and TNF-α levels. Treatment of BCP and LA showed a significant decrease in oxidative stress and down-regulated the cardiac expression of NF-ĸβ. Thus, the combination of BCP with LA improves cardiac functions by attenuating inflammation through NF-ĸβ inhibition in DCM.

Heart Failure Probability and Early Outcomes of Critically Ill Patients With COVID-19: A Prospective, Multicenter Study

Background: The relationship between cardiac functions and the fatal outcome of coronavirus disease 2019 (COVID-19) is still largely underestimated. We aim to explore the role of heart failure (HF) and NT-proBNP in the prognosis of critically ill patients with COVID-19 and construct an easy-to-use predictive model using machine learning.Methods: In this multicenter and prospective study, a total of 1,050 patients with clinical suspicion of COVID-19 were consecutively screened. Finally, 402 laboratory-confirmed critically ill patients with COVID-19 were enrolled. A “triple cut-point” strategy of NT-proBNP was applied to assess the probability of HF. The primary outcome was 30-day all-cause in-hospital death. Prognostic risk factors were analyzed using the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression, further formulating a nomogram to predict mortality.Results: Within a 30-day follow-up, 27.4% of the 402 patients died. The mortality rate of patients with HF likely was significantly higher than that of the patient with gray zone and HF unlikely (40.8% vs. 25 and 16.5%, respectively, P < 0.001). HF likely [Odds ratio (OR) 1.97, 95% CI 1.13–3.42], age (OR 1.04, 95% CI 1.02–1.06), lymphocyte (OR 0.36, 95% CI 0.19–0.68), albumin (OR 0.92, 95% CI 0.87–0.96), and total bilirubin (OR 1.02, 95% CI 1–1.04) were independently associated with the prognosis of critically ill patients with COVID-19. Moreover, a nomogram was developed by bootstrap validation, and C-index was 0.8 (95% CI 0.74–0.86).Conclusions: This study established a novel nomogram to predict the 30-day all-cause mortality of critically ill patients with COVID-19, highlighting the predominant role of the “triple cut-point” strategy of NT-proBNP, which could assist in risk stratification and improve clinical sequelae.

SUMO-specific Isopeptidases Tuning Cardiac SUMOylation in Health and Disease

SUMOylation is a transient posttranslational modification with small-ubiquitin like modifiers (SUMO1, SUMO2 and SUMO3) covalently attached to their target-proteins via a multi-step enzymatic cascade. SUMOylation modifies protein-protein interactions, enzymatic-activity or chromatin binding in a multitude of key cellular processes, acting as a highly dynamic molecular switch. To guarantee the rapid kinetics, SUMO target-proteins are kept in a tightly controlled equilibrium of SUMOylation and deSUMOylation. DeSUMOylation is maintained by the SUMO-specific proteases, predominantly of the SENP family. SENP1 and SENP2 represent family members tuning SUMOylation status of all three SUMO isoforms, while SENP3 and SENP5 are dedicated to detach mainly SUMO2/3 from its substrates. SENP6 and SENP7 cleave polySUMO2/3 chains thereby countering the SUMO-targeted-Ubiquitin-Ligase (StUbL) pathway. Several biochemical studies pinpoint towards the SENPs as critical enzymes to control balanced SUMOylation/deSUMOylation in cardiovascular health and disease. This study aims to review the current knowledge about the SUMO-specific proteases in the heart and provides an integrated view of cardiac functions of the deSUMOylating enzymes under physiological and pathological conditions.