Health-Stress-Disease Triangle. Pathophysiological Focus and Perspectives

CAPURRO CLAUDIA; LUIS SOBREVIA ; MARIA CECILIA LAROCCA ; GRACIELA ALICIA CREMASCHI ; MARTIN VILA PETROFF

Frontiers in Physiology

Front. Physiol. Sec. Integrative Physiology

Año: 2024 vol. 15

1664-042X

Basic and clinical studies have proved the efficacy of anti-inflammatory therapies in theprevention of cardiovascular (CV) diseases of different aetiology. Accordingly,inflammation has recently emerged as a potential mediator of CV disease. However,despite numerous investigations highlighting the causal role of inflammation incardiovascular pathophysiology, inflammation is an extremely complex phenomenon inwhich specific cellular mechanisms of action remain elusive. In this Research Topic, thereview article by González and colleagues focuses on the critical cardiovascular effects ofthe inflammatory mediator Galectin-3 (Gal-3) and sheds light on its potential therapeuticbenefit to reduce CV disease. Gal-3 belongs to the family, of beta-galactoside-bindingproteins, and is involved in many biological processes including inflammation. The role ofGal-3 in inflammation is multifaceted and paradoxical as both pro-inflammatory and antiinflammatory responses have been reported. However, Gonzalez et al. compellingly clarifythe diversity of inflammatory actions of Gal-3 in the pathological settings of myocardialinfarction, hypertension, atherosclerosis, and aging. Although the available literatureprovides some contradictory results, the consensus points to Gal-3 as a pro-inflammatorymolecule with an active role in the development of fibrosis, atherosclerotic plaque, adverseremodelling, and myocardial contractile dysfunction. In this scenario, Gal-3 inhibitorsemerge as innovative cardiovascular therapeutic agents with clinical perspectives.Pro- and anti-inflammatory responses depend not only on the molecular nature of theinflammatory mediator but also on the balance between pro- and anti-inflammatoryimmune cells. Thus, cell-to-cell interaction arises as a pivotal player shaping theinflammatory response. An exquisite example of this intricate interplay is revealed in thearticle published by Gonzalez Bosc and colleagues where the altered balance between proinflammatory T helper 17 (TH17) cells and anti-inflammatory regulatory T cells (Tregs) isshown to orchestrate a pro-inflammatory microenvironment that is essential for thedevelopment of pulmonary hypertension (PH). The study demonstrates that in response tochronic hypoxia there is a switch of Treg to TH17 cells, denominated exTreg-TH17 cells,which tilts the Treg–TH17 cell balance toward TH17 cells, creating a pro-inflammatoryenvironment. These results suggest that therapies aimed at restoring active Tregs andpreventing the transition of exTreg-to-TH17 cells could be a potential avenue for thetreatment of PH.Ischemic heart disease constitutes a major cause of death worldwide and in thispathological setting, inflammation has also been shown to play a critical role. Similarly,reactive oxygen species (ROS) contribute significantly to ischemia-reperfusion (IR) injury.Ischemic preconditioning is a strategy whereby brief episodes of ischemia by occlusion ofa coronary artery followed by reperfusion, activate endogenous protective mechanismsand decrease IR damage. Cardiac protection also occurs when brief preconditioningischemic episodes occur in a distant tissue, such as a limb, which is termed remoteischemic preconditioning (RIPC). Multiple lines of evidence indicate that inhibition of NLRfamily pyrin domain containing 3 (NLRP3)-inflammasome-dependent inflammation andNADPH oxidase type 2 (NOX2)-dependent ROS production prevents ischemicpreconditioning. However, there is scarce information on the participation of thesepathways in RIPC. In this topic issue of Frontiers in Physiology, the study by Sánchez andcolleagues convincingly demonstrates that RIPC activates NOX2 and the NLRP3In reviewinflammasome resulting in a secondary antioxidant and anti-inflammatory response thatconfers protection against myocardial IR injury. In depth understanding of the molecularmechanisms of cardiac protection as those shown in this topic issue, pave the way to theachievement of novel protective protocols that may prove beneficial for the treatment ofpatients exposed to IR injury.Another critical player in IR injury is intracellular Ca2+ overload. Enhanced Ca2+ entry via theL-type Ca2+ channels is a major contributor to this cation overload. The study of the impactof Ca2+ channel inhibitors on IR injury is a vibrant and controversial area of research.Inhibition of Ca2+ channels has been shown to be effective to ameliorate post-ischemicdamage in animal and cellular models of IR. However, the clinical use of Ca2+ channelblockers in myocardial infarct is still in dispute because of their marked hemodynamiceffects. Thus, the search for novel and safer compounds that specifically interfere with Ca2+entry is ongoing. In this issue, Mosca and colleagues discuss the use of an alternativecompound, N-methylacetazolamide (NMA), with potential benefits to those or classicalCa2+ channel antagonists. NMA is derived from the carbonic anhydrase (CA) inhibitoracetazolamide. The substitution of a methyl group for an H+in the sulfonamide moiety ofacetazolamide results in a loss of its CA inhibitory property while maintaining the physicalchemical properties of acetazolamide. In animal models of cardiac IR, NMA was shown tosignificantly reduce infarct size and diastolic stiffness and to increase systolic function.These beneficial effects were attributed to a direct inhibitory effect of NMA on the pore ofthe Ca2+ channel. Although the mechanism of action of NMA seems to be shared withclassical L-type Ca2+ channel blockers, the fact that NMA was shown to have protectivefeatures even when given during reperfusion represents an attractive alternative toameliorate post ischemic impairment. This possibility makes NMA a unique tool for thetreatment of ischemic heart disease in patients. Future clinical trials will be mandatory todemonstrate the effectiveness of NMA in humans and its advantages or disadvantages incomparison to other Ca2+ antagonists. Considering the causal role of inflammation in IRinjury, and the existing evidence showing that Ca2+ overload triggers inflammation, furtherinvestigation examining the capacity of NMD to mitigate inflammation is warranted.As we dive into the depth of the physiological findings of the articles published in thisspecial issue, the important contribution of SAFIS and ALACF to the knowledge of thisdisciplinary area is reflected. As we transition from one article to the next, we immerseourselves in groundbreaking research, fostered by international collaboration and enrichedby both basic and clinical perspectives. Each page breaths an educational atmosphere,inviting readers to explore new physiological discoveries and push the boundaries of ourunderstanding.