Molecular Signaling to Preserve Mitochondrial Integrity against Ischemic Stress in the Heart: Rescue or Remove Mitochondria in Danger

Cardiovascular diseases are one of the leading causes of death and global health problems worldwide, and ischemic heart disease is the most common cause of heart failure (HF). The heart is a high-energy demanding organ, and myocardial energy reserves are limited. Mitochondria are the powerhouses of the cell, but under stress conditions, they become damaged, release necrotic and apoptotic factors, and contribute to cell death. Loss of cardiomyocytes plays a significant role in ischemic heart disease. In response to stress, protective signaling pathways are activated to limit mitochondrial deterioration and protect the heart. To prevent mitochondrial death pathways, damaged mitochondria are removed by mitochondrial autophagy (mitophagy). Mitochondrial quality control mediated by mitophagy is functionally linked to mitochondrial dynamics. This review provides a current understanding of the signaling mechanisms by which the integrity of mitochondria is preserved in the heart against ischemic stress.

Elovanoids downregulate SARS-CoV-2 cell-entry, canonical mediators and enhance protective signaling in human alveolar cells

The pro-homeostatic lipid mediators elovanoids (ELVs) attenuate cell binding and entrance of the SARS-CoV-2 receptor-binding domain (RBD) as well as of the SARS-CoV-2 virus in human primary alveoli cells in culture. We uncovered that very-long-chain polyunsaturated fatty acid precursors (VLC-PUFA, n-3) activate ELV biosynthesis in lung cells. Both ELVs and their precursors reduce the binding to RBD. ELVs downregulate angiotensin-converting enzyme 2 (ACE2) and enhance the expression of a set of protective proteins hindering cell surface virus binding and upregulating defensive proteins against lung damage. In addition, ELVs and their precursors decreased the signal of spike (S) protein found in SARS-CoV-2 infected cells, suggesting that the lipids curb viral infection. These findings open avenues for potential preventive and disease-modifiable therapeutic approaches for COVID-19.

Implications of Oxidative and Nitrosative Post-Translational Modifications in Therapeutic Strategies against Reperfusion Damage

Post-translational modifications based on redox reactions “switch on-off” the biological activity of different downstream targets, modifying a myriad of processes and providing an efficient mechanism for signaling regulation in physiological and pathological conditions. Such modifications depend on the generation of redox components, such as reactive oxygen species and nitric oxide. Therefore, as the oxidative or nitrosative milieu prevailing in the reperfused heart is determinant for protective signaling, in this review we defined the impact of redox-based post-translational modifications resulting from either oxidative/nitrosative signaling or oxidative/nitrosative stress that occurs during reperfusion damage. The role that cardioprotective conditioning strategies have had to establish that such changes occur at different subcellular levels, particularly in mitochondria, is also presented. Another section is devoted to the possible mechanism of signal delivering of modified proteins. Finally, we discuss the possible efficacy of redox-based therapeutic strategies against reperfusion damage.

Apoptosis in resistance arteries induced by hydrogen peroxide: greater resilience of endothelium versus smooth muscle

Reactive oxygen species (ROS) are implicated in cardiovascular and neurologic disorders including atherosclerosis, heart attack, stroke, and traumatic brain injury. Although oxidative stress can lead to apoptosis of vascular cells, such findings are largely based upon isolated vascular smooth muscle cells (SMCs) and endothelial cells (ECs) studied in culture. Studying intact resistance arteries, we have focused on understanding how SMCs and ECs in the blood vessel wall respond to acute oxidative stress induced by hydrogen peroxide, a ubiquitous, membrane-permeant ROS. We find that apoptosis induced by H2O2 is far greater in SMCs compared to ECs. For both cell types, apoptosis is associated with a rise in intracellular calcium concentration ([Ca2+]i) during H2O2 exposure. Consistent with their greater death, the rise in [Ca2+]i for SMCs exceeds that in ECs. Finding that disruption of the endothelium increases SMC death, we address how myoendothelial coupling and paracrine signaling attenuate apoptosis. Remarkably, conditions associated with chronic oxidative stress (advanced age, Western-style diet) protect SMCs during H2O2 exposure, as does female sex. In light of intracellular Ca2+ handling, we consider how glycolytic versus oxidative pathways for ATP production and changes in mitochondrial structure and function impact cellular resilience to H2O2-induced apoptosis. Gaining new insight into protective signaling within and between SMCs and ECs of the arterial wall can be applied to promote vascular cell survival (and recovery of blood flow) in tissues subjected to acute oxidative stress as occurs during reperfusion following myocardial infarction and thrombotic stroke.

Elovanoids downregulate canonical SARS-CoV-2 cell-entry mediators and enhance protective signaling in human alveolar cells

The pro-homeostatic lipid mediators elovanoids (ELVs) attenuate cell binding and entrance of the SARS-CoV-2 receptor-binding domain (RBD) in human primary alveoli cells in culture. We uncovered that very-long-chain polyunsaturated fatty acid precursors (VLC-PUFA,n-3) activate ELV biosynthesis in lung cells. Both ELVs and their precursors reduce the binding to RBD. ELVs downregulate angiotensin-converting enzyme 2 (ACE2) and enhance the expression of a set of protective proteins hindering cell surface virus binding and upregulating defensive proteins against lung damage. These findings open avenues for potential preventive and disease-modifiable therapeutic approaches for COVID-19.

Reaction Cycles of Halogen Species in the Immune Defense: Implications for Human Health and Diseases and the Pathology and Treatment of COVID-19

There is no vaccine or specific antiviral treatment for COVID-19, which is causing a global pandemic. One current focus is drug repurposing research, but those drugs have limited therapeutic efficacies and known adverse effects. The pathology of COVID-19 is essentially unknown. Without this understanding, it is challenging to discover a successful treatment to be approved for clinical use. This paper addresses several key biological processes of reactive oxygen, halogen and nitrogen species (ROS, RHS and RNS) that play crucial physiological roles in organisms from plants to humans. These include why superoxide dismutases, the enzymes to catalyze the formation of H2O2, are required for protecting ROS-induced injury in cell metabolism, why the amount of ROS/RNS produced by ionizing radiation at clinically relevant doses is ~1000 fold lower than the endogenous ROS/RNS level routinely produced in the cell and why a low level of endogenous RHS plays a crucial role in phagocytosis for immune defense. Herein we propose a plausible amplification mechanism in immune defense: ozone-depleting-like halogen cyclic reactions enhancing RHS effects are responsible for all the mentioned physiological functions, which are activated by H2O2 and deactivated by NO signaling molecule. Our results show that the reaction cycles can be repeated thousands of times and amplify the RHS pathogen-killing (defense) effects by 100,000 fold in phagocytosis, resembling the cyclic ozone-depleting reactions in the stratosphere. It is unraveled that H2O2 is a required protective signaling molecule (angel) in the defense system for human health and its dysfunction can cause many diseases or conditions such as autoimmune disorders, aging and cancer. We also identify a class of potent drugs for effective treatment of invading pathogens such as HIV and SARS-CoV-2 (COVID-19), cancer and other diseases, and provide a molecular mechanism of action of the drugs or candidates.

Osteopontin and Integrin Mediated Modulation of Post-Synapses in HIV Envelope Glycoprotein Exposed Hippocampal Neurons

The advent of Human Immunodeficiency Virus (HIV) antiretrovirals have reduced the severity of HIV related neurological comorbidities but they nevertheless remain prevalent. Synaptic degeneration due to the action of several viral factors released from infected brain myeloid and glia cells and inflammatory cytokines has been attributed to the manifestation of a range of cognitive and behavioral deficits. The contributions of specific pro-inflammatory factors and their interplay with viral factors in the setting of treatment and persistence are incompletely understood. Exposure of neurons to chemokine receptor-4(CXCR4)-tropic HIV-1 envelope glycoprotein (Env) can lead to post-synaptic degradation of dendritic spines. The contribution of members of the extracellular matrix (ECM) and specifically, of perineuronal nets (PNN) toward synaptic degeneration, is not fully known, even though these structures are found to be disrupted in post-mortem HIV-infected brains. Osteopontin (Opn, gene name SPP1), a cytokine-like protein, is found in abundance in the HIV-infected brain. In this study, we investigated the role of Opn and its ECM integrin receptors, β1- and β3 integrin in modifying neuronal synaptic sculpting. We found that in hippocampal neurons incubated with HIV-1 Env protein and recombinant Opn, post-synaptic-95 (PSD-95) puncta were significantly increased and distributed to dendritic spines when compared to Env-only treated neurons. This effect was mediated through β3 integrin, as silencing of this receptor abrogated the increase in post-synaptic spines. Silencing of β1 integrin, however, did not block the increase of post-synaptic spines in hippocampal cultures treated with Opn. However, a decrease in the PNN to βIII-tubulin ratio was found, indicating an increased capacity to support spine growth. From these results, we conclude that one of the mechanisms by which Opn counters the damaging impact of the HIV Env protein on hippocampal post-synaptic plasticity is through complex interactions between Opn and components of the ECM which activate downstream protective signaling pathways that help maintain the potential for effective post-synaptic plasticity.

Resveratrol and Diabetic Cardiomyopathy: Focusing on the Protective Signaling Mechanisms

Diabetic cardiomyopathy (DCM) is a common cardiovascular complication of diabetic mellitus that is characterized by diastolic disorder in the early stage and clinical heart failure in the later stage. Presently, DCM is considered one of the major causes of death in diabetic patients. Resveratrol (RSV), a naturally occurring stilbene, is widely reported as a cardioprotective substance in many heart diseases. Thus far, the specific roles of RSV in DCM prevention and treatment have attracted great attention. Here, we discuss the roles of RSV in DCM by focusing its downstream targets from both in vivo and in vitro studies. Among such targets, Sirtuins 1/3 and AMP-activated kinase have been identified as key mediators that induce cardioprotection during hyperglycemia. In addition, many other signaling molecules (e.g., forkhead box-O3a and extracellular regulated protein kinases) are also regulated in the presence of RSV and exert beneficial effects such as opposing oxidative stress, inflammation, and apoptosis in cardiomyocytes exposed to high-glucose conditions. The beneficial potential of an RSV/stem cell cotherapy is also reviewed as a promising therapeutic strategy for preventing the development of DCM.

Thrombomodulin Regulation of Mitogen-Activated Protein Kinases

The multifaceted role of mitogen-activated protein kinases (MAPKs) in modulating signal transduction pathways in inflammatory conditions such as infection, cardiovascular disease, and cancer has been well established. Recently, coagulation factors have also emerged as key players in regulating intracellular signaling pathways during inflammation. Among coagulation factors, thrombomodulin, as a high affinity receptor for thrombin on vascular endothelial cells, has been discovered to be a potent anti-inflammatory and anti-tumorigenic signaling molecule. The protective signaling function of thrombomodulin is separate from its well-recognized role in the clotting cascade, which is to function as an anti-coagulant receptor in order to switch the specificity of thrombin from a procoagulant to an anti-coagulant protease. The underlying protective signaling mechanism of thrombomodulin remains largely unknown, though a few published reports link the receptor to the regulation of MAPKs under different (patho)physiological conditions. The goal of this review is to summarize what is known about the regulatory relationship between thrombomodulin and MAPKs.