Remote ischemic conditioning as a cytoprotective strategy in vasculopathies during hyperhomocysteinemia: An emerging research perspective

Abstract

Higher levels of nonprotein amino acid homocysteine (Hcy), that is, hyperhomocysteinemia (HHcy) (~5% of general population) has been associated with severe vasculopathies in different organs; however, precise molecular mechanism(s) as to how HHcy plays havoc with body’s vascular networks are largely unknown. Interventional modalities have not proven beneficial to counter multifactorial HHcy’s effects on the vascular system. An ancient Indian form of exercise called ‘yoga’ causes transient ischemia as a result of various body postures however the cellular mechanisms are not clear. We discuss a novel perspective wherein we argue that application of remote ischemic conditioning (RIC) could, in fact, deliver anticipated results to patients who are suffering from chronic vascular dysfunction due to HHcy. RIC is the mechanistic phenomenon whereby brief episodes of ischemia‐reperfusion events are applied to distant tissues/organs; that could potentially offer a powerful tool in mitigating chronic lethal ischemia in target organs during HHcy condition via simultaneous reduction of inflammation, oxidative and endoplasmic reticulum stress, extracellular matrix remodeling, fibrosis, and angiogenesis. We opine that during ischemic conditioning our organs cross talk by releasing cellular messengers in the form of exosomes containing messenger RNAs, circular RNAs, anti‐pyroptotic factors, protective cytokines like musclin, transcription factors, small molecules, anti‐inflammatory, antiapoptotic factors, antioxidants, and vasoactive gases. All these could help mobilize the bone marrow–derived stem cells (having tissue healing properties) to target organs. In that context, we argue that RIC could certainly play a savior’s role in an unfortunate ischemic or adverse event in people who have higher levels of the circulating Hcy in their systems.

Effect of Methionine Diet on Time-Related Metabolic and Histopathological Changes of Rat Hippocampus in the Model of Global Brain Ischemia

“…The ROS caused by hHcy can react with biological molecules that can lead to the irreversible alternations of their ultimate functions (sometimes even rendering them completely inactive). HHcy state abnormally activated MMP-9, degraded the components of the extracellular matrix as well as the gap junction protein connexin-43, thereby causing fibrosis and vascular dysfunction [ 71 ]. The other potential mechanism is a structural protein modification due to the N-homocysteinylation which presents a covalent modification of Hcy thiolactone and results in the protein denaturation, enzymatic inactivation and even amyloid formation that inhibits endothelial function, thus establishing a vicious cycle for impairing brain circulation [ 33 ] that is associated with neurodegenerative diseases [ 35 ].…”

Restoration of skeletal muscle homeostasis by hydrogen sulfide during hyperhomocysteinemia-mediated oxidative/ER stress condition

“…K ATP channel activation has been suggested to be involved in the prevention of calcium overload and preservation of myofibre integrity during exercise, as well as recovery from muscle fatigue, rather than in normal muscle contractility and excitability (MacIntosh et al 2012; Matar et al 2000). Similarly, a significant decrease in H 2 S content in muscle fibers, together with a reduction in SOD1 expression, was presented in a rat model of skeletal muscle ischemiareperfusion (I-R) injury (Du et al 2013; Majumder et al 2019).…”

Genes and genetics in hyperhomocysteinemia and the “1-carbon metabolism”: implications for retinal structure and eye functions

“…More often, the ocular manifestations of HHcy are serious and can potentially lead to loss of eyesight and blindness. This article sums up the findings concerning roles of genetics in HHcy that are relevant in various ocular disorders and how to effectively manage them (Ding et al 2012;Eloranta et al 1990;Finkelstein 1990;Majumder et al 2018aMajumder et al , 2018bMajumder et al , 2018c.…”