Prevention of export of anoxia/reoxygenation injury from ischemic to nonischemic cardiomyocytes via inhibition of endocytosis

Abstract

Myocardial infarct size is determined by the death of nonischemic border zone cardiomyocytes caused by export of injury signals from the infarct zone. The countermeasures to limit infarct size, therefore, should be aimed at nonselective blockade of most, if not all, injury signals from entering nonischemic cells. To test whether inhibition of endocytosis might limit infarct size, HL-1 cardiomyocytes were subjected to anoxia (6 h) and reoxygenation (1 h). Anoxic and reoxygenated cells showed a multifold increase in mitochondrial ROS production accompanied with upregulation of scavenger receptors lectin-like oxidized low-density lipoprotein receptor-1 and CD36 and stimulation of stress signals, including NADPH oxidase subunit p22(phox), SOD2, and beclin-1. Incubation of healthy cardiomyocytes in media from anoxic and reoxygenated cells (conditioned media) resulted in qualitatively similar responses, including increase in the generation of mitochondrial ROS, p22(phox), SOD2, and beclin-1. Anoxia and reoxygenation caused collapse of clathrin-mediated endocytosis and stimulation of macropinocytosis, whereas in cultures exposed to conditioned media, the activity of endocytosis was uniformly higher. Conditioned media also significantly aggravated cytotoxic effects of TNF-α and angiotensin II, and suppression of endocytosis reversed these trends, resulting in an overall increase of metabolic activity. Moreover, inhibition of endocytosis prevented binding of oxidized cellular fragments with greater efficiency than targeted neutralization of the scavenger receptor lectin-like oxidized low-density lipoprotein receptor-1. Many of the observations in HL-1 cardiomyocytes were confirmed in primary cardiomyocyte cultures. Our data suggest that endocytosis is upregulated in border zone cardiomyocytes, and inhibition of endocytosis may be an effective approach to prevent export of injury signals from the infarct zone.

Prazosin protects myocardial cells against anoxia-reoxygenation injury via the extracellular signal‑regulated kinase signaling pathway

“…In the current study, the efficacy of prazosin against anoxia-reoxygenation injury in a mouse model was investigated. The results demonstrated that prazosin decreases the plasma concentration of inflammatory factors, and improves oxidative stress in myocardial cells ( 26 ). Notably, it was observed that prazosin treatment exerts significant anti-apoptotic effects in myocardial cells of mice models of anoxia-reoxygenation injury.…”

Complex Effects of Putative DRP-1 Inhibitors on Stress Responses in Mouse Heart and Rat Cardiomyoblasts

“…The 1 mM concentration applied in hearts is thus considered to be relatively selective for dynamin/DRP-1 inhibition. Higher concentrations are employed to inhibit endocytosis, which may participate in either cardiac injury ( Khaidakov et al, 2014;Yang et al, 2016) or protection (Most et al, 2003). Yang et al (2016) found, for example, that 80 mM dynasore reduced internalization of cardioprotective ATPsensitive potassium channels and infarct development during myocardial I-R.…”

Circulating MicroRNA Profiles Differ between Qi‐Stagnation and Qi‐Deficiency in Coronary Heart Disease Patients with Blood Stasis Syndrome

“…In addition, it is evidenced that the cellular rate of nutrient or ion uptake (e.g., glucose, Fe 3+ , and K + ) or efflux (e.g., Na + ) is governed by a complement of membrane transporters and receptors that show dynamic localization at both the plasma membrane and the defined intracellular membrane compartments [ 18 ]. Some research showed that endocytosis was upregulated in border zone cardiomyocytes, and inhibition of endocytosis might be an effective approach to prevent export of injury signals from the myocardial infarct size [ 19 ]. In considering endocytosis as the most obvious upregulated pathway in QDB, we speculate that endocytosis process consumes excessive the above mentioned nutrients so that the body appears a series of energy deficiency signs, as so-called Qi-deficiency.…”