Scientists have found that the new coronavirus S protein induces long-term transcriptional inhibition of myocardial mitochondrial metabolism genes and leads to impaired myocardial fibrosis and contractile function

Researchers at the University Medical Center in Ulm, Germany, issued an article saying that BA.
5's ability to replicate in human cardiomyocytes and damage cardiomyocytes is stronger than BA.
1, more similar to the Delta variant, once again confirming that the new coronavirus can infect and damage cardiomyocytes [1].

However, the specific mechanism by which the new coronavirus damages the heart muscle remains unclear
.

Recently, a research team led by Wenbin Tan, an associate professor at the University of South Carolina School of Medicine, published the latest research results [2] on the preprint platform bioRxiv, which answered our questions
from the mechanism.

They found that in obese mice induced by a high-fat diet, the S protein of the new coronavirus can induce long-term transcriptional inhibition of genes related to mitochondrial metabolism in cardiomyocytes, and lead to myocardial fibrosis and damage to contractility
.
This discovery has given us a deeper understanding
of coronavirus-related cardiomyopathy.

▲ Screenshot of the first page of the paper

In order to explore the mechanism of cardiomyopathy caused by the new crown, Wenbin Tan's team constructed the S protein pseudo (Spp) virus based on the early original new crown strain and studied
it in human skin capillary endothelial cells (HDMVECs), macrophages (MØ) and cardiomyocyte-like H9C2 cells.

Based on the above three cell lines, they found that low-density lipoprotein cholesterol (LDL-c) has a very high affinity with Spp, LDL-c can combine class B type 1 scavenger receptor (SR-B1) on the cell surface to enhance Spp's ability to enter cells, and SR-B1 inhibitor BLT-1 can inhibit LDL-c to enhance Spp's ability
to enter cells.
This is also consistent with previous research results [3].

LDL-c and SR-B1 promote the entry of Spp virus into cells

Wenbin Tan's team then studied the selectivity
of the Spp virus to the heart in normal diet (NCF) mice and high-fat diet (HFD) mice.

Considering that the previous experiment found that LDL-c and SR-B1 were closely related to the efficiency of Spp virus entering cells, the researchers first analyzed the levels of LDL-c in the serum of two groups of mice, as well as the expression of SR-B1 in cells of
different tissues and organs.

There is no doubt that the serum levels of total cholesterol, LDL-c, and very low LDL-c in mice in the high-fat diet group were significantly higher than in the normal diet group
.

The expression of SR-B1 came as a surprise, and compared with mice in the normal diet group, the high-fat diet group had significantly increased levels of SR-B1 protein in heart, adipose tissue and kidney cells, but not in liver, lung and spleen cells
.
Correspondingly, compared with mice in the normal diet group, mice in the high-fat diet group selectively increased significantly in the heart, kidney, aorta and adipose tissue two hours after vaccination with Spp virus, and still accumulated
in the heart, aorta and adipose tissue after 24 hours.

▲ Levels of Spp virus in different tissues and organs in different dietary patterns

The Spp virus used by Wenbin Tan's team is not capable of replication, and under normal circumstances, intracellular virus levels should decline over time
.
But after 24 hours, virus levels in the heart, aorta and adipose tissue are still increasing or at high levels
.
This also suggests that the Spp virus is extremely selective about these
tissues.

The next question is what effect the Sepp virus selectively accumulates in cardiomyocytes and what effect
it will have on cardiomyocytes.
To answer this question, Wenbin Tan's team explored the underlying mechanisms
at the differential expression (DE) level of the gene.

In mice on a normal diet, there were differences in expression of 30 genes in the myocardium of mice 24 hours after vaccination with Spp virus compared with the control group not vaccinated with Spp virus, of which 19 were upregulated and 11 were down-regulated
.
They believe that the changes in normal-diet mice are milder because the virus in the heart is almost eliminated after 24 hours [4].

After 24 hours of vaccination with SPP virus, there were still 548 genes with unvaccinated high-fat diet mice, and 434 genes were different from normal diet mice vaccinated with the virus
.
It can be seen that the effect of Spp virus on myocardial gene expression in mice on high-fat diet mice is very violent
.

▲ Effect of SPP virus on cardiomyocyte gene expression in mice on high-fat diet

Building on the above research, Wenbin Tan's team also explored the long-term effects
of Spp virus on cardiomyocytes gene expression and the heart muscle itself.

They found that 3 weeks after vaccination with the Spp virus, there were no differentially expressed genes between normal diet mice, but there were still 209 differentially expressed genes in high-fat diet mice, of which 69 were upregulated and 140 were down-regulated
.
In-depth analysis showed that most of the down-regulated genes had electron transfer activity and proton transmembrane transport activity, while most of the up-regulated genes had GTPase activity and GTP binding ability
.

Notably, three gene families involved in the mitochondrial respiratory chain (MRC) were significantly downregulated, including ATP synthetase, NADH:ubiquinone oxidoreductase family (NDUFs), and cytochrome c oxidase (COX).

▲ Effect of SPP virus on mitochondrial respiratory chain in cardiomyocytes

Six weeks after inoculating with the Spp virus, Wenbin Tan's team observed cardiac fibrosis in mice
.
In normal diet mice, regardless of whether they have been vaccinated with the virus, there is no difference
in the fibrosis of the hearts of the two groups after 6 weeks.
The high-fat diet mice vaccinated with Spp virus had obvious fibrosis
in the myocardium.

▲ Myocardial fibrosis after 6 weeks

At 24 weeks after inoculation, Wenbin Tan's team studied heart function
in mice by ultrasound.

They found that mice on a high-fat diet had a significant decrease in cardiac ejection fraction (EF) and shortened fraction (FS) at 24 weeks of vaccination with Spp virus compared to an age-matched high-fat diet control, while left ventricular end-systolic diameter and volume increased
significantly.
This indicates a decrease in the ability of the heart muscle to contract and damage
to the heart muscle.

Overall, this study by Wenbin Tan's team shows that LDL-c can enhance the ability of viruses to enter cells, and that high-fat diet-induced obesity can lead to selective accumulation of viruses in heart, aorta, and adipose tissue; Subsequently, the S protein of the virus causes long-term transcriptional inhibition of the mitochondrial respiratory chain gene family, resulting in abnormal myocardial metabolism; Finally, myocardial fibrosis increases, and function is impaired
.

Coincidentally, around the same time, a study published in Circulation by the teams of David R.
Walt and Lael M.
Yonker at Harvard University also pointed to the S protein [5].

▲ Screenshot of the first page of the paper

This study found that free full-length S protein that was not bound to antibodies could be detected in the blood of adolescents and young adults who developed myocarditis after mRNA vaccination, while free S protein was not detected in the population without myocarditis [5].

It is not difficult to see that this study supports to some extent the mechanism
of myocardial damage discovered by Wenbin Tan's team.

Heart damage and cardiomyopathy, as common complications of the new coronavirus infection, have been the focus
of scientists.
Both studies presented today suggest that the S protein may play an important role
in this.
However, since the S protein is the fastest mutating part of the new coronavirus, more research
is needed on whether different subtypes of the new coronavirus have similar mechanisms.

In any case, after recovering from the new crown virus, we still have to pay attention to rest and give the body more time to repair
.

I wish all infected people a speedy recovery
.

References:

[1].
Nchioua R, Diofano F, Noettger S, et al.
Strong attenuation of SARS-CoV-2 Omicron BA.
1 and increased replication of the BA.
5 subvariant in human cardiomyocytes.
Signal Transduct Target Ther.
2022; 7(1):395.
doi:10.
1038/s41392-022-01256-9

[2].
Xiaoling Cao, Vi Nguyen, Joseph Tsai, et al.
The SARS-CoV-2 Spike protein induces long-term transcriptional perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and reduces myocardial contractile in obese mice.
bioRxiv 2023.
01.
05.
522853; doi: https://doi.
org/10.
1101/2023.
01.
05.
522853

[3].
Wei C, Wan L, Yan Q, et al.
HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry.
Nat Metab.
2020; 2(12):1391-1400.
doi:10.
1038/s42255-020-00324-0

[4].
Cao X, Tian Y, Nguyen V, et al.
Spike protein of SARS-CoV-2 activates macrophages and contributes to induction of acute lung inflammation in male mice.
FASEB J.
2021; 35(9):e21801.
doi:10.
1096/fj.
202002742RR

[5].
Yonker LM, Swank Z, Bartsch YC, et al.
Circulating Spike Protein Detected in Post-COVID-19 mRNA Vaccine Myocarditis.
Circulation.
2023.
doi:10.
1161/CIRCULATIONAHA.
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061025