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Mechanism of Blood-Heart-Barrier Leakage: Implications for COVID-19 Induced Cardiovascular Injury.
- Source :
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International journal of molecular sciences [Int J Mol Sci] 2021 Dec 17; Vol. 22 (24). Date of Electronic Publication: 2021 Dec 17. - Publication Year :
- 2021
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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.
- Subjects :
- Animals
Blood virology
Blood Physiological Phenomena immunology
COVID-19 physiopathology
Cardiomegaly metabolism
Cardiovascular Diseases metabolism
Cardiovascular Physiological Phenomena immunology
Disease Models, Animal
Endothelium metabolism
Heart physiopathology
Heart Failure virology
Hydroxychloroquine pharmacology
Male
Matrix Metalloproteinase 9 drug effects
Matrix Metalloproteinase 9 metabolism
Mice
Mice, Inbred C57BL
Muscle Cells metabolism
Myocardium metabolism
SARS-CoV-2 metabolism
SARS-CoV-2 pathogenicity
Ventricular Remodeling physiology
COVID-19 complications
Heart virology
Heart Failure metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 34948342
- Full Text :
- https://doi.org/10.3390/ijms222413546