APN-sEVs to protect against Cardiovascular diseases
APN-sEVs, with of all their proven properties, show great promise as a treatment for cardiovascular diseases
Overview
Cardiovascular diseases (CVD) are a major cause of morbidity and mortality worldwide, representing the leading cause of death globally with over 17.9 million lives lost each year[1] ; by 2030, this number is expected to increase to >22.2 million. The vast majority of cardiovascular events are attributed to atherosclerosis, in which lipid plaques form in the vessel walls. CVD has been extensively associated with chronic low-grade inflammation[2] and involvement of both innate and adaptive immunity with macrophages as principal actors.
[1] https://www.who.int/health-topics/cardiovascular-diseases#tab=tab_1
[2] Henein MY et al. Int J Mol Sci. 2022. doi: 10.3390/ijms232112906.
Evidence of Cardiovascular Protection by Adiponectin
LOW LEVELS OF ADIPONECTIN IN ISCHEMIC HEART DISEASE
Low levels of adiponectin are strongly linked to obesity-related cardiovascular diseases like ischemic heart disease[1],[2] and this reduction has been proposed to have a crucial role in the pathogenesis of atherosclerosis and cardiovascular diseases associated with obesity and the metabolic syndrome[3]. Although adipocytes are the major contributor to plasma adiponectin, the adipokine is also expressed in cardiomyocytes.
[1] Pischon T et al. JAMA. 2004. doi: 10.1001/jama.291.14.1730.
[2] Kosmas CE et al. J Int Med Res. 2023. doi: 10.1177/03000605231164548.
[3] Yanai H et al. Int J Mol Sci. 2019. doi: 10.3390/ijms20051190.
CVD TREATMENTS INCREASE CIRCULATING LEVELS OF ADIPONECTIN
Adiponectin protects against hypertension, atherosclerosis, heart failure. adiponectin exerts its cardiovascular protective effects through direct actions on the heart as well as on several types of vascular cells. Some approved pharmacological interventions that benefit cardiovascular disorders are also associated with increased adiponectin levels. For instance, using PPARγ agonists results in a significant increase in circulating adiponectin levels.[4].
[4] Iwaki M et al. Diabetes. 2003 . doi: 10.2337/diabetes.52.7.1655.
Adiponectin Mode of Action in CVD
Adiponectin exerts its vascular protective effects through its direct actions on almost all the major types of cells present in blood vessels, including endothelial cells, endothelial progenitor cells (EPC), macrophages, smooth muscle cells, platelet, and leukocytes.
Adiponectin exerts its cardioprotective effects through the activation of multiple signaling pathways in cardiomyocytes[5]. First, the antiapoptotic effect is mediated by the AdipoR ceramidase activity, Akt, and AMPK. Second, anti-ROS-induced cell remodeling is achieved by activating AMPK while inhibiting ERK and NF-κB signaling activity[6]. Third, the anti-inflammatory action is mediated by the activation of sphingosine kinase 1 and cyclooxygenase 2. Additionally, adiponectin stimulates: 1) glucose uptake via Akt-induced plasma membrane translocation of GLUT4, and 2) lipid uptake via AMPK-mediated upregulation of CD36.
[5] Xu A, Vanhoutte PM. Am J Physiol Heart Circ Physiol, 2012. doi:10.1152/ajpheart.00765.2011.
[6] Essick EE et al. Am J Physiol Heart Circ Physiol, 2011. doi:10.1152/ajpheart.00428.2011.
INSULIN SENSITIVIZING EFFECTS
Insulin resistance has been established as a risk factor for CV events[7]. This alteration of insulin signaling pathways results in the development of cardiometabolic disorders, including obesity, dyslipidemia, low-grade inflammation, endothelial dysfunction and hypertension, all of which are predisposing factors for atherosclerosis and CVD. Adiponectin reduces inflammatory cytokines and oxidative stress, which leads to an improvement of insulin resistance. This contributes to reduce hepatic glucose production and increase the utilization of glucose and fatty acids by skeletal muscles, lowering blood glucose levels.
[7] Kosmas CEet al. J Int Med Res. 2023. doi: 10.1177/03000605231164548.
ANTI-ATHEROSCLEROTIC PROPERTIES
Adiponectin concentration is associated with lipoprotein metabolism; specifically it increases HDL and decreases TG[8]. Adiponectin also has anti-atherosclerotic properties, including reducing scavenger receptors in macrophages and increasing cholesterol efflux. The adiponectin/T-cadherin complex was shown to provide cardiovascular protection by enhancing exosome production and releasing toxic substances from specific cell types within the vasculature.
[8] Yanai H, Yoshida H. Int J Mol Sci. 2019. doi: 10.3390/ijms20051190.
Potential benefits of APN-sEVs in cardiovascular protection
APN-sEVs have several functions and properties in vivo that will be highly beneficial in CVD treatment:
- APN-sEVs improve overall insulin sensitivity
- APN-sEVs reduce oxidative stress
- APN-sEVs reduce tissue inflammation
- APN-sEVs reduce lipogenesis
- APN-sEVs preserve muscle mass
