Mechanism of Blood-Heart-Barrier Leakage: Implications for COVID-19 Induced Cardiovascular Injury.

Rubens P Homme,Mahavir Singh,Akash K George,Sathnur Pushpakumar,Irina Smolenkova,Suresh C Tyagi,Yuting Zheng

doi:10.3390/ijms222413546

Abstract

Although blood–heart-barrier (BHB) leakage is the hallmark of congestive (cardio-pulmonary) heart failure (CHF), the primary cause of death in elderly, and during viral myocarditis resulting from the novel coronavirus variants such as the severe acute respiratory syndrome novel corona virus 2 (SARS-CoV-2) known as COVID-19, the mechanism is unclear. The goal of this project is to determine the mechanism of the BHB in CHF. Endocardial endothelium (EE) is the BHB against leakage of blood from endocardium to the interstitium; however, this BHB is broken during CHF. Previous studies from our laboratory, and others have shown a robust activation of matrix metalloproteinase-9 (MMP-9) during CHF. MMP-9 degrades the connexins leading to EE dysfunction. We demonstrated juxtacrine coupling of EE with myocyte and mitochondria (Mito) but how it works still remains at large. To test whether activation of MMP-9 causes EE barrier dysfunction, we hypothesized that if that were the case then treatment with hydroxychloroquine (HCQ) could, in fact, inhibit MMP-9, and thus preserve the EE barrier/juxtacrine signaling, and synchronous endothelial-myocyte coupling. To determine this, CHF was created by aorta-vena cava fistula (AVF) employing the mouse as a model system. The sham, and AVF mice were treated with HCQ. Cardiac hypertrophy, tissue remodeling-induced mitochondrial-myocyte, and endothelial-myocyte contractions were measured. Microvascular leakage was measured using FITC-albumin conjugate. The cardiac function was measured by echocardiography (Echo). Results suggest that MMP-9 activation, endocardial endothelial leakage, endothelial-myocyte (E-M) uncoupling, dyssynchronous mitochondrial fusion-fission (Mfn2/Drp1 ratio), and mito-myocyte uncoupling in the AVF heart failure were found to be rampant; however, treatment with HCQ successfully mitigated some of the deleterious cardiac alterations during CHF. The findings have direct relevance to the gamut of cardiac manifestations, and the resultant phenotypes arising from the ongoing complications of COVID-19 in human subjects.

Highlights

Researchers have started investigating that it is important to determine the mechanism of BHB leakage if the same are involved in various disease conditions including the viral infections, including the COVID-19 that infect vital organs such heart [1,8,9,10,11,12,13,14]
The findings suggested that EF was attenuated during aorta-vena cava fistula (AVF), but interestingly, the treatment with HCQ mitigated this attenuation of cardiac ejection function in CHF (Figure 9)
The primary cause of CHF leading to death during old age and viral myocarditis is not fully understood

Summary

Introduction

Numerous studies have focused on CHF, but a very few have determined the BHB function [1] The endothelium, whether it is in the endocardium or in a coronary or capillary, is the primary barrier against BHB dysfunction [2,3,4]. Regarding the tightjunction proteins such as connexin-37 between endothelial-endothelial, connexin-43 between endothelial-myocyte, myocyte-myocyte and mitochondria (mito)-myocyte are the primary connexins [5,6,7] In this context, researchers have started investigating that it is important to determine the mechanism of BHB leakage if the same are involved in various disease conditions including the viral infections, including the COVID-19 that infect vital organs such heart [1,8,9,10,11,12,13,14]. The basement membrane between endothelium and muscle contains ECM, encompassing the latent

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