Communication Between Cardiomyocytes and Fibroblasts During Cardiac Ischemia/Reperfusion and Remodeling: Roles of TGF-β, CTGF, the Renin Angiotensin Axis, and Non-coding RNA Molecules

Abstract

Communication between cells is a foundational concept for understanding the physiology and pathology of biological systems. Paracrine/autocrine signaling, direct cell-to-cell interplay, and extracellular matrix interactions are three types of cell communication that regulate responses to different stimuli. In the heart, cardiomyocytes, fibroblasts, and endothelial cells interact to form the cardiac tissue. Under pathological conditions, such as myocardial infarction, humoral factors released by these cells may induce tissue damage or protection, depending on the type and concentration of molecules secreted. Cardiac remodeling is also mediated by the factors secreted by cardiomyocytes and fibroblasts that are involved in the extensive reciprocal interactions between these cells. Identifying the molecules and cellular signal pathways implicated in these processes will be crucial for creating effective tissue-preserving treatments during or after reperfusion. Numerous therapies to protect cardiac tissue from reperfusion-induced injury have been explored, and ample pre-clinical research has attempted to identify drugs or techniques to mitigate cardiac damage. However, despite great success in animal models, it has not been possible to completely translate these cardioprotective effects to human applications. This review provides a current summary of the principal molecules, pathways, and mechanisms underlying cardiomyocyte and cardiac fibroblast crosstalk during ischemia/reperfusion injury. We also discuss pre-clinical molecules proposed as treatments for myocardial infarction and provide a clinical perspective on these potential therapeutic agents.

Intracellular Toxic Advanced Glycation End-Products May Induce Cell Death and Suppress Cardiac Fibroblasts

“…Moreover, we demonstrated that intracellular TAGE induces cell death in HCF. Based on the previous studies, we considered that death of HCF directly inhibited the role of them more than the suppression of HCF activation or differentiation [ 3 , 4 , 5 , 6 ].…”

“…Cardiovascular disease (CVD) is a lifestyle-related disease (LSRD) caused by the dysfunction and cell death of cardiomyocytes via ischemic or non-ischemic events [ 1 , 2 , 3 ]. Cardiac fibroblasts are crucial for the repair and remodeling of the heart.…”

“…When injured, cardiomyocytes release cell-specific signaling molecules, such as cytoplasmic contents, cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, and growth factors, such as transforming growth factor (TGF)-β, which activate cardiac fibroblasts and induce their differentiation into cardiac myofibroblasts. Activated cardiac fibroblasts and cardiac myofibroblasts secrete connective tissue growth factor to promote antioxidant effects in cardiomyocytes [ 3 ], and proteins, such as collagen, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs to protect the cardiac tissue integrity [ 3 , 4 , 5 ]. In contrast, angiotensin II and TGF-β secreted from activated cardiac fibroblasts promote the production of reactive oxygen species by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and induce apoptosis in cardiomyocytes [ 3 ].…”

“…Activated cardiac fibroblasts and cardiac myofibroblasts secrete connective tissue growth factor to promote antioxidant effects in cardiomyocytes [ 3 ], and proteins, such as collagen, matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs to protect the cardiac tissue integrity [ 3 , 4 , 5 ]. In contrast, angiotensin II and TGF-β secreted from activated cardiac fibroblasts promote the production of reactive oxygen species by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and induce apoptosis in cardiomyocytes [ 3 ]. Moreover, excessive secretion of collagen, connective tissue growth factor, angiotensin II, and TGF-β induce fibrosis in cardiac tissue [ 4 , 5 , 6 ].…”

“…GA is generated from glucose and fructose in the heart via three pathways that require aldose reductase, sorbitol dehydrogenase, ketohexokinase, and aldolase B [ 2 , 9 , 10 ]. The cardiac fibroblasts account for approximately 60–70% of cardiac cells [ 3 ]. Based on these findings, we hypothesized that intracellular TAGE is generated in cardiac fibroblasts, which induces their dysfunction or death, while extracellular TAGE may exhibit cytotoxicity via the receptor for AGEs (RAGE) [ 11 ].…”