Circulating cardiomyocyte-derived extracellular vesicles reflect cardiac injury during systemic inflammatory response syndrome in mice

Abstract

The release of extracellular vesicles (EVs) is increased under cellular stress and cardiomyocyte damaging conditions. However, whether the cardiomyocyte-derived EVs eventually reach the systemic circulation and whether their number in the bloodstream reflects cardiac injury, remains unknown. Wild type C57B/6 and conditional transgenic mice expressing green fluorescent protein (GFP) by cardiomyocytes were studied in lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome (SIRS). EVs were separated both from platelet-free plasma and from the conditioned medium of isolated cardiomyocytes of the left ventricular wall. Size distribution and concentration of the released particles were determined by Nanoparticle Tracking Analysis. The presence of GFP + cardiomyocyte-derived circulating EVs was monitored by flow cytometry and cardiac function was assessed by echocardiography. In LPS-treated mice, systemic inflammation and the consequent cardiomyopathy were verified by elevated plasma levels of TNFα, GDF-15, and cardiac troponin I, and by a decrease in the ejection fraction. Furthermore, we demonstrated elevated levels of circulating small- and medium-sized EVs in the LPS-injected mice. Importantly, we detected GFP+ cardiomyocyte-derived EVs in the circulation of control mice, and the number of these circulating GFP+ vesicles increased significantly upon intraperitoneal LPS administration (P = 0.029). The cardiomyocyte-derived GFP+ EVs were also positive for intravesicular troponin I (cTnI) and muscle-associated glycogen phosphorylase (PYGM). This is the first direct demonstration that cardiomyocyte-derived EVs are present in the circulation and that the increased number of cardiac-derived EVs in the blood reflects cardiac injury in LPS-induced systemic inflammation (SIRS).

Single-cell transcriptomics reveal extracellular vesicles secretion with a cardiomyocyte proteostasis signature during pathological remodeling

“…As such, this could ultimately limit the pathogenesis and the onset of misfolding associated disease mechanisms, and in perspective, represent a potential target to develop novel therapeutic intervention 70 . It may be interesting to identify the presence of these EVs in the circulating blood as previously demonstrated in cardiomyocyte-derived EVs, which were present in the circulation and reflecting cardiac injury that can serve as biomarker of cardiac injury 71 , 72 . The EVs protein cargo composition associated with proteostasis functions of the cardiomyocytes make them attractive potential biomarkers to detect cardiac health 73 .…”

Mitochondria Dysfunction at the Heart of Viral Myocarditis: Mechanistic Insights and Therapeutic Implications

“…In the absence of active viral infection, the excess presence of MDVs in circulation has been recognized as a potential marker for the development of cardiovascular disease, particularly in patients with metabolic disorders, such as type 2 diabetes, insulin resistance, and atherosclerosis [ 130 ]. Similarly, increased amount of cardiomyocyte-derived extracellular vesicles and mitochondria was detected in circulation following cardiac injury [ 131 ]. A key step in MDV production is vesicle fragmentation/division from the mitochondrial network, which has been observed in several clinical settings, including DCM, congenital heart disease, and heart failure [ 132 ].…”

Mitochondrial cargo export in exosomes: Possible pathways and implication in disease biology

“…In contrast to healthy mt induced repair function, oxidatively damaged mt (whole or in part) can be exported in exosomes of injured CMC. A study by Hegyasi et al (2022) found that injured CMC preferentially secrete mt‐enriched LEVs which are detectable in circulation and represent diagnostic value. Although, little is known about the diagnostic utility of mt‐enREXO in cardio biology, few initial studies are indicative of its clinical predictive value especially during trauma or heart surgery where local cardiac vascular beds display a surge in mt‐DNA loaded plasma exosomes (Baysa et al, 2019).…”