Exosomes in Cardiovascular Diseases: Pathological Potential of Nano-Messenger

Abstract

Cardiovascular diseases (CVDs) represent a major global health problem, due to their continued high incidences and mortality. The last few decades have witnessed new advances in clinical research which led to increased survival and recovery in CVD patients. Nevertheless, elusive and multifactorial pathophysiological mechanisms of CVD development perplexed researchers in identifying efficacious therapeutic interventions. Search for novel and effective strategies for diagnosis, prevention, and intervention for CVD has shifted research focus on extracellular vesicles (EVs) in recent years. By transporting molecular cargo from donor to recipient cells, EVs modulate gene expression and influence the phenotype of recipient cells, thus EVs prove to be an imperative component of intercellular signaling. Elucidation of the role of EVs in intercellular communications under physiological conditions implied the enormous potential of EVs in monitoring and treatment of CVD. The EVs secreted from the myriad of cells in the cardiovascular system such as cardiomyocytes, cardiac fibroblasts, cardiac progenitor cells, endothelial cells, inflammatory cells may facilitate the communication in physiological and pathological conditions. Understanding EVs-mediated cellular communication may delineate the mechanism of origin and progression of cardiovascular diseases. The current review summarizes exosome-mediated paracrine signaling leading to cardiovascular disease. The mechanistic role of exosomes in cardiovascular disease will provide novel avenues in designing diagnosis and therapeutic interventions.

Keywords: atherosclerosis; cardiovascular disease; exosomes; extracellular vesicles; heart failure.

Figure 1

Exosome-mediated paracrine signaling and development of vascular diseases. Exosome secreted by endothelial cells, inflammatory cells, and the myriad of circulating blood cells leads to endothelial dysfunction and inflammation and subsequently, the development of vascular diseases such as atherosclerosis, peripheral artery disease, and pulmonary arterial hypertension.

Figure 2

Role of exosomes in development of peripartum cardiomyopathy and cardiac hypertrophy. Antiangiogenic 16 kDa fragment, 16K PRL, is generated in peripartum cardiomyopathy patients by cathepsin D-mediated cleavage of prolactin (PRL). 16K PRL stimulates cardiac fibroblasts and endothelial cells to secrete miR-146a enriched exosomes which upon transferring miR-146a to cardiomyocytes lead to impaired metabolism and angiogenesis in cardiomyocytes. miR-21*-enriched exosomes secreted by cardiac fibroblasts, under stress conditions, elevate miR-21* in cardiomyocytes. This results in cardiomyocyte hypertrophy by downregulation of SORBS2 and PDLIM5 expression levels.

Figure 3

Exosome-assisted development of septic cardiomyopathy and diabetic hypertrophy. In response to high levels of lipopolysaccharide (LPS) and nitric oxide (NO) in sepsis, platelets secrete inflammatory exosomes with reduced miR-233 and are enriched in NADPH oxidase, nitric oxide synthases (NOS), and protein disulfide isomerase (PDI). This induces apoptosis in endothelial cells and cardiomyocytes via activation of reactive oxygen/ nitrogen species (ROS/RNS) signaling pathways, caspase 3 activation, thereby leading to cardiomyopathy. Exosomes secreted from diabetic cardiomyocytes contain increased levels of miR-320. Uptake of exosomal miR-320 by endothelial cells results in increased levels of Hsp20, IGF-1, and Ets2, thus, inhibiting angiogenesis in diabetic hearts.