Abstract
This review summarizes data from several laboratories that have demonstrated a role of the Na/K-ATPase, specifically its α1 subunit, in the generation of reactive oxygen species (ROS) via the negative regulator of Src. Together with Src and other signaling proteins, the Na/K-ATPase forms an oxidant amplification loop (NKAL), amplifies ROS, and participates in cytokines storm in obesity. The development of a peptide fragment of the α1 subunit, NaKtide, has been shown to negatively regulate Src. Several groups showed that the systemic administration of the cell permeable modification of NaKtide (pNaKtide) or its selective delivery to fat tissue—adipocyte specific expression of NaKtide—ameliorate the systemic elevation of inflammatory cytokines seen in chronic obesity. Severe acute respiratory syndrome – coronavirus 2 (SARS-CoV-2), the RNA Coronavirus responsible for the COVID-19 global pandemic, invades cells via the angiotensin converting enzyme 2 (ACE-2) receptor (ACE2R) that is appended in inflamed fat tissue and exacerbates the formation of the cytokines storm. Both obesity and heart and renal failure are well known risks for adverse outcomes in patients infected with COVID-19. White adipocytes express ACE-2 receptors in high concentration, especially in obese patients. Once the virus invades the white adipocyte cell, it creates a COVID19–porphyrin complex which degrades and produces free porphyrin and iron and increases ROS. The increased formation of ROS and activation of the NKAL results in a further potentiated formation of ROS production, and ultimately, adipocyte generation of more inflammatory mediators, leading to systemic cytokines storm and heart failure. Moreover, chronic obesity also results in the reduction of antioxidant genes such as heme oxygenase-1 (HO-1), increasing adipocyte susceptibility to ROS and cytokines. It is the systemic inflammation and cytokine storm which is responsible for many of the adverse outcomes seen with COVID-19 infections in obese subjects, leading to heart failure and death. This review will also describe the potential antioxidant drugs and role of NaKtide and their demonstrated antioxidant effect used as a major strategy for improving obesity and epicardial fat mediated heart failure in the context of the COVID pandemic.
Highlights
These positive effects were shown to increase with the dosage inhibitor, has been shown to effectively block the Na/K-ATPase oxidant amplification loop, improving the outcome and decreasing risk of a number of diseases associated to oxidative stress such as obesity, steatohepatitis, atherosclerosis, and cancer. pNaKtide has been shown to improve outcomes in ischemia-reperfusion related heart disease and ameliorate pathological changes seen in uremic cardiomyopathy [49,86]
In the context of COVID-19 infection, this can result in further oxidative insult that contributes to heart failure in these patients
Excess pericardial fat found in obesity increases inflammatory cytokines near the heart, in a similar manner to the inflammatory cytokine storm seen in COVID-19 infection
Summary
SARS-CoV-2, the virus responsible for COVID-19, is causing a worldwide pandemic that has currently infected over 16 million people with more than 600,000 deaths. The virus binds ACE2 receptor, and porphyrin by means of the so called spike protein on the virus capside [7] This leads to increased levels of free heme and a reduction in functional hemoprotein, with a resultant increase in inflammatory reactions. The redox state of adipocytes has been shown to regulate the progression of uremic cardiomyopathy in partially nephrectomized mice This means that oxidative stress, caused by increased carbonylation of the Na/K-ATPase α1 subunit and the subsequent increased activity of Src, may contribute to renal failure and subsequent renal-cardiac syndrome [11]. Both COVID-19 and obesity have deep, adverse effects on cardiac function. The increased iron levels can overwhelm the cytoprotective capacity of HO-1, resulting in the formation of reactive oxygen species (ROS) [26] and augmented carbonylation of the Na/K-ATPase α1 subunit
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