Extracellular Endothelial Cell-Derived Vesicles: Emerging Role in Cardiac and Vascular Remodeling in Heart Failure

Abstract

Extracellular vesicles play a pivotal role in numerous physiological (immune response, cell-to-cell cooperation, angiogenesis) and pathological (reparation, inflammation, thrombosis/coagulation, atherosclerosis, endothelial dysfunction) processes. The development of heart failure is strongly associated with endothelial dysfunction, microvascular inflammation, alteration in tissue repair, and cardiac and vascular remodeling. It has been postulated that activated endothelial cell-derived vesicles are not just transfer forms of several active molecules (such as regulatory peptides, coagulation factors, growth factors, active molecules, hormones that are embedded onto angiogenesis, tissue reparation, proliferation, and even prevention from ischemia/hypoxia), but are instead involved in direct myocardial and vascular damage due to regulation of epigenetic responses of the tissue. These responses are controlled by several factors, such as micro-RNAs, that are transferred inside extracellular vesicles from mother cells to acceptor cells and are transductors of epigenetic signals. Finally, it is not a uniform opinion whether different phenotypes of heart failure are the result of altered cardiac and vascular reparation due to certain epigenetic responses, which are yielded by co-morbidities, such as diabetes mellitus and obesity. The aim of the review is to summarize knowledge regarding the role of various types of extracellular endothelial cell-derived vesicles in the regulation of cardiac and vascular remodeling in heart failure.

Emerging Role of Adipocyte Dysfunction in Inducing Heart Failure Among Obese Patients With Prediabetes and Known Diabetes Mellitus

“…Adipose tissue comprises various depots including WAT, BAT, and other ectopic adipose tissues including thoracic, epicardial, abdominal, retroperitoneal, and perivascular adipose tissues. The phenotype of thoracic and epicardial adipose tissue resembles BAT, whereas both molecularity and functionality of abdominal, retroperitoneal, and perivascular adipose tissues do not distinguish WAT ( 24 , 25 ).…”

“…Although cell-free RNAs in human serum have been present in higher concentrations to ECVs, half biotypes of coding and non-coding RNA (micro-RNA, transfer RNA, small yRNA, circular RNA, and long non-coding RNA) are transferred with ECVs. There is evidence of the assumption that different phenotypes of HF are the result of altered cardiac and vascular reparation due to certain epigenetic responses, which are yielded by AO and DM ( 24 ). The genetic material and active molecules that are in ECVs are transductors of epigenetic signals and thereby regulate remodeling ( 203 ).…”

“…Although the number of various subtypes of ECVs especially originated from endothelial cells correlated well with BMI and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) ( 205 ), there are a limiting number of non-coding RNAs, such as hsa-miR-423-5p, rno-miR-16, rno-miR-20b, rno-miR-93, rno-miR-106b, rno-miR-223, hsa-miR-660-3p, hsa-miR-665, hsa-miR-1285-3p, and hsa-miR-4491, which was strongly associated with the development of HFpEF ( 206 ). Some of the muscle-specific circulating miRNAs (hsa-miR-423-5p, rno-miR-16, rno-miR-20b) and others contribute to interstitial fibrosis (hsa-miR-665, hsa-miR-1285-3p, and hsa-miR-4491), IR (miR-141-3p), and inflammation (miR-4763-3p) ( 24 ). Based on the current knowledge of RNA regulatory networks, multiple ECV-derived non-coding RNAs definitely ensure cell-to-cell communications and mediate tissue response, i.e., cardiac and vascular remodeling, endothelial dysfunction, and browning adipose tissue.…”

“…Therefore, the systemic effects of white (WAT) and brown adipose tissue (BAT) can be different, and adipogenesis including browning of adipose tissue and deficiency of anti-inflammatory adipocytokines was strongly associated with adipose triglyceride lipase augmentation, altered glucose homeostasis, resistance to insulin of skeletal muscles, increased cardiac myocyte apoptosis, and lowered survival and function of progenitor endothelial cells, which could significantly influence on HF development, as well as end-organ fibrosis and multiple comorbidities ( 21 ). However, whether the adipocytokine dysfunction is crucial for adverse maladaptive cardiac and vascular remodeling and development of different phenotypes of HF is uncertain and is under investigation so far ( 22 – 24 ). Finally, the role of adipocyte dysfunction in the association between AO and survival advantage in HF is not certain.…”

Immuno-Surgical Management of Pancreatic Cancer with Analysis of Cancer Exosomes

“…Moreover, EVs are reportedly involved in other diseases than cancer, such as modulating metabolic diseases, like type 2 diabetes mellitus [ 56 ], amyotrophic lateral sclerosis [ 57 ], heart failure [ 58 ] and stroke [ 59 ]. It is known that these secreted EVs are circulated in peripheral blood, so considerable efforts have focused on the possibility that the clinical examination of EVs may be useful for diagnosing and monitoring human diseases [ 60 ].…”