Hypoxic Epicardium Contribution to Myocardial Repair

Dergilev Konstantin V; Menshikov Mikhail Yu; Parfyonova Yelena V

doi:10.37871/jbres1829

ISSN: 2766-2276

Medicine Group. 2023 November 14;4(11):1552-1556. doi: 10.37871/jbres1829.

Subject area(s)

Cardiovascular Diseases
Clinical Cardiology

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Mini Review

Hypoxic Epicardium Contribution to Myocardial Repair

Dergilev Konstantin V, Menshikov Mikhail Yu* and Parfyonova Yelena V

National Medical Research Center for Cardiology named after academician Yevgeniy Chazov of the Ministry of Health of the Russian Federation, Academician Chazov Str., 15a. Moscow, Russia

*Corresponding author: Menshikov Mikhail Yu, National Medical Research Center for Cardiology named after academician Yevgeniy Chazov of the Ministry of Health of the Russian Federation, Academician Chazov Str., 15a. Moscow, Russia E-mail:

Received: 30 October 2023 | Accepted: 12 November 2023 | Published: 14 November 2023

How to cite this article: Dergilev KV, Menshikov MY, Parfyonova YV. Hypoxic Epicardium Contribution to Myocardial Repair. J Biomed Res Environ Sci. 2023 Oct 14; 4(11): 1552-1556. doi: 10.37871/jbres1757, Article ID: jbres1757

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Summary

Epicardium, the outer epithelial layer of the heart forming from extracardiac primordium, plays a fundamental role in myocardial embryogenesis by generating epicardial-derived cells (cardiac fibroblasts, mesenchymal cells, vascular smooth muscle cells). In the adult heart, epicardium occurs as a mesothelial layer, which, in injured heart, recalls its “embryonic program” and transforms into mesenchymal cells contributing, by such a way, to myocardial reparation. This process is facilitated by hypoxic conditions arising during injury. In general, regulation of this process may be a potential methodology for treatment of cardiovascular diseases.

The improvement of post-myocardial infarction therapy requires the development of new targeted treatment methodology. Among the different approaches, the usage of inner myocardial resources is a perspective strategy for elaborating the effective cellular therapy [1,2]. Multiple studies had demonstrated that the epicardium, a leaflet covering myocardium, plays a significant role in both heart development and regeneration [3-5]. During myocardial embryogenesis epicardium, forming from extracardial primordium, participates in formation of cardiac tissue by producing epicardial-derived cells (cardiac fibroblasts, mesenchymal cells, vascular smooth muscle cells and cardiomyocytes [6].

In the adult heart the epicardium differentiates into a dormant layer of epithelial-like (mesothelial) cells lining the outer myocardium and coronary vessels. However, when heart injury, like myocardial infarction occurs, epicardium reactivates its developmental program, by transforming to mesenchymal state. In the native (uninjured) epicardial regions adjacent to the damaged tissue, a number of changes occur characterizing the enhancement of their proliferative, secretory and expression activity. The main event attracting the attention of many researchers is Epithelial-Mesenchymal Transition (EMT), a complex process leading to a change of phenotype and appearance of mesenchymal cells. The main characteristic of EMT is the loss of apicobasal polarity of epithelial cells, loss of intercellular contacts (due to decreased expression of E-cadherin, the main factor ensuring intercellular interactions), as well as the acquisition by cells of the ability to proliferate, migrate and invade.

EMT is a complex process involving several signaling pathways triggered by growth factors. Transforming Growth Factor-beta (TGFβ) as well as Bone Morphogenic Protein (BMP) phosphorylate SMAD transcription factors [7]; Platelet-Derived Growth Factor (PDGF), Fibroblast Growth Factors (FGFs), Epidermal Growth Factor (EGF), Insulin-Like Growth Factor (IGF), and Hepatocyte Growth Factor (HGF), by acting via their specific receptors, activate ERK/MAPK and PI3K/Akt kinase signal pathways [8]. Wnt/β-catenin signaling initiates gene transcription by releasing beta-catenin from the inhibitory complex containing Glycogen Synthase Kinase GSK3β [9].

These signaling mechanisms converge on the expression of EMT transcription factors (SNAIL, ZEB, TWIST and some others) which, in turn, repress epithelial marker genes (E-cadherin, claudins, occludin) and activate genes belonging to mesenchymal phenotype (fibronectin, vitronectin, N-cadherin, matrix metalloproteinases) [10-12]. Although complete recapitulation of epicardial embryonic program is not achieved on cardiac injury, the epicardium, due to EMT, contributes significantly to myocardial repair after infarction [13].

The appearance of novel techniques such as single cell RNA sequencing permitted to visualize a heterogeneity of cell populations, epicardial cells as well [14,15] which can be subdivided into different clusters. In particular, epicardial heterogeneity, which was observed earlier, is closely related to distribution of different factors in diverse cellular subpopulations [15]. It was also found that epicardial markers, EMT factors, cardiomyogenesis-associated genes, HIF-1 responsive genes, paracrine factors can be non-uniformly distributed in different clusters reflecting very complicated interrelationship between cellular subpopulations in the composition of tissue.

Epicardium, as well as some other cell populations in a number of tissues, has been characterized as a hypoxic niche [16-18]. The concept of hypoxic niche also extends to the microenvironment of some cancer [19] and progenitor cells [20]. The development of hypoxia in the epicardium is exacerbated when cardiac tissue is damaged, due to the destruction of the vascular network that provides oxygen delivery to cells. Sharp hypoxia damages epicardium and myocardium, however, it triggers reparative processes. Hypoxia by itself is inducer of cardiac reparation [21].

Multiple effects of hypoxia at the cellular level are exerted by multipotent transcription factor, Hypoxia-Inducible Factor 1-alpha (HIF-1α), which can bind to many promoter sites of a great number genes. HIF-1α, among other factors, is a powerful inducer of EMT [22]. In addition, HIF-1α is a master regulator of cell metabolism. Under normoxia HIF-1α, expressing in all tissues, is rapidly inactivated through O2-dependent hydroxylation by prolyl hydroxylase followed by its degradation [23]. In hypoxic conditions, it’s up-regulation occurs due to protein stabilization. In turn, stabilization of HIF-1α leads to increased expression of factors whose genes contain Hypoxia-Responsive Elements (HREs) in their promoter.

HIF-1α induces expression of the majority enzymes participating in glycolytic metabolic pathway: aldolase, enolase, lactate dehydrogenase [24,25], Phosphoglycerate Dehydrogenase Kinase 1 (PDK1) [26], Glucose-6-Phosphate Isomerase (GPI1), Glyceraldehyde Phosphate Dehydrogenase (GAPDH) [27,28], Lactate Dehydrogenase (LDHA), phosphofructokinase (PFK1) and fructose 1, 6-bisphosphatase [29], Triose Phosphatidyl Isomerase (TPI1) [30].

Stimulation of glycolytic genes by HIF-1, which initiates the rearrangement of cellular glucose metabolism to lactate, is important for preserving cell viability under hypoxia. In addition, under these conditions, control over mitochondrial activity is also very important, since generation of reactive oxygen species by them can cause cell death. In this regard, it is quite remarkable HIF-1-dependent stimulation of the expression of Pyruvate Dehydrogenase Kinase (PDK1). PDK inhibits the activity of pyruvate dehydrogenase complex which produces acetyl-coenzyme A, a necessary component of tricarbonic acid cycle of mitochondria [26,31], thus preventing the activity of the mitochondrial pathway of glucose utilization.

As it is mentioned above, HIF1 is a powerful stimulant of EMT which activates expression of a number of EMT-related factors [32-34]. In this regard, a key role can belong to glyceraldehyde phosphate dehydrogenase that, in addition to its participation in glycolysis, is also involved into EMT regulation through interaction with SP1 transcription factor and, by such a way, enhancement of SNAIL expression in colon cancer cells [35]. A role of another glycolytic enzyme, Pyruvate Kinase M2 (PKM2) in regulating the EMT is mediated through its interaction in nucleus with TGF-β-Induced Factor Homeobox 2 (TGIF2), a repressor of TGF-β signaling. PKM2 binding with TGIF2 recruits histone deacetylase 3 to the E-cadherin promoter sequence leading to suppression of E-cadherin transcription [36].

The role of HIF-1 as a hypoxic factor has another aspect, which is that HIF-1 enhances the activation of myeloid cells, increasing the process of glycolysis in them, as well as inducing the secretion of proinflammatory cytokines [37-39]. Since the development of inflammation is the primary response to tissue damage, the role of HIF-1 as an inflammatory factor may be an essential complement to its overall proregenerative effect. In addition, it is noteworthy that HIF-1 and HIF-1-dependent genes expression is not distributed uniformly in epicardial tissue [15], reflecting the situation of functional heterogeneity between different cell subpopulations.

As a conclusion, the epitheial-to-mesenchymal transition, a multifactorial process contributing to both detrimental (tumor growth and metastasis) and beneficial (tissue regeneration/reparation) effects, needs to be studied in respect of its up- and down-regulation. Due to significant contribution of HIF-1 signaling to EMT, this factor should be accounted as a modifier of cellular signal transduction, expression and secretion mechanisms depending on cellular microenvironment. In addition, a cellular energy metabolism along with external factors can be regarded as a cause influencing cellular activity and fate.