A microRNA network is the putative mediator of reductive stress in the
heart
Understanding how reductive stress is controlled may help personalize treatment of heart failure patients, leading to better outcomes

Date:
August 6, 2021
Source:
University of Alabama at Birmingham
Summary:
Last year, researchers reported that reductive stress -- an
imbalance in the normal oxidation/reduction homeostasis -- caused
pathological changes associated with heart failure in a mouse
model. Now, researchers describe the putative molecular regulators
of this pathological chronic reductive stress -- a microRNA network.



FULL STORY ==========================================================================
Last year, University of Alabama at Birmingham researchers reported
that reductive stress -- an imbalance in the normal oxidation/reduction homeostasis -- caused pathological changes associated with heart failure
in a mouse model.

This was a follow-up to their 2018 clinical study that about one in six
heart failure patients shows reductive stress.


==========================================================================
Now, in the journal Scientific Reports, researchers describe the putative molecular regulators of this pathological chronic reductive stress --
a microRNA network.

Redox balance is vital for health. Oxidative stress has long been linked
to heart failure, the progressive weakening of the heart muscle that
can lead to death, though attempts at antioxidant therapy have been ineffectual. The finding that reductive stress can also lead to heart
pathology may help personalize treatment of heart failure patients,
leading to better outcomes.

Human microRNAs, or miRNAs, are short, non-coding RNAs with about
22 bases.

They act to regulate gene expression by a complementary pairing with
specific messenger RNAs of the cell. That pairing silences the messenger
RNA, preventing them from being translated into a protein. Thus, miRNAs
are a fine-tuned controller of cell metabolism or the cell's response
to stress and adverse challenges, like oxidative stress in the heart.

The current research, led by Rajasekaran Namakkal-Soorappan, Ph.D.,
associate professor in the UAB Department of Pathology, used mice that overexpress Nrf2, pronounced "nerf-two," in cardiomyocytes to identify
the miRNA network.

Nrf2 is a master transcriptional regulator that confers short-term
protection - - by helping express genes for antioxidant activity --
for heart muscle cells when reactive oxygen and nitrogen species are
created as blood flow returns after a heart attack. However, persistent
Nrf2 activation can paradoxically result in reductive stress.



==========================================================================
The researchers had recently shown that Nrf2 deficiency inhibited the expression of several miRNAs in the heart, suggesting a relationship
between Nrf2 expression and miRNAs. So, they now decided to look for
changes in miRNA levels in three mouse models -- one with normal Nrf2
and two that constitutively overexpress Nrf2, at either low or high
levels. Overexpression of both leads to pathological heart remodeling.

Comparison of miRNA levels from the three models identified a subset of
miRNAs that appeared to be a direct and dose-dependent target of Nrf2,
and thus putative regulators of reductive stress. Namakkal-Soorappan calls these miRNAs reductomiRs, pronounced "reducto-meers." The researchers
also identified dose-dependent genes that were differentially expressed
in the hearts of mice that overexpress Nrf2. Because miRNAs silence gene expression at the post-transcriptional level, the researchers believed
that this distinct subset of genes could represent reductomiR targets
for negative regulation.

Next, they looked for a link between the reductomiRs and the genes. In
normal function, Nrf2 promotes the expression of genes that contain
a DNA sequence called the "antioxidant response element" located near
their promoters. With genomic software tools, the researchers probed
the DNA of the mouse genome to find sequences for miRNAs that also had
an antioxidant response element near their promoters.

They then used bioinformatics tools to identify 19 miRNAs that exhibited complementary sequences to the seed sequences in 61 down-regulated differentially expressed genes. These 19 miRNAs thus appear to
be reductomiRs that mediate Nrf2-responsive myocardial reductive
stress. Other computational tools also were used to create an integrative, Nrf2-responsive miRNA-mRNA functional network that shows putative nodes
of differentially expressed genes.

Namakkal-Soorappan calls the reductomiRs only putative mediators because
the analyses in the current study resulted from bioinformatics. Needed
next, he says, are mechanistic studies to confirm functions of the
mediators.

Co-first authors of the study, "Identification of Nrf2-responsive
microRNA networks as putative mediators of myocardial reductive stress,"
are Justin M.

Quiles and Mark E. Pepin, UAB Department of Pathology, Division of
Molecular and Cellular Pathology.

Co-authors, along with corresponding author Namakkal-Soorappan, are
Sini Sunny, Sandeep B. Shelar, Anil K. Challa and Adam R. Wende, UAB
Department of Pathology; Brian Dalley and John R. Hoidal, University of
Utah; and Steven M.

Pogwizd, UAB Department of Medicine Comprehensive Cardiovascular Center.

Support came from National Institutes of Health grants 2HL118067,
HL118067, AG042860, HL133011, HL007918 and HL137240; American Heart
Association grant BGIA 0865015F; a University of Utah Center for Aging
Pilot Grant; the University of Utah; UAB; and an Alexander von Humboldt Foundation postdoctoral fellowship.

========================================================================== Story Source: Materials provided by
University_of_Alabama_at_Birmingham. Original written by Jeffrey
Hansen. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Justin M. Quiles, Mark E. Pepin, Sini Sunny, Sandeep B. Shelar,
Anil K.

Challa, Brian Dalley, John R. Hoidal, Steven M. Pogwizd,
Adam R. Wende, Namakkal S. Rajasekaran. Identification of
Nrf2-responsive microRNA networks as putative mediators of
myocardial reductive stress. Scientific Reports, 2021; 11 (1)
DOI: 10.1038/s41598-021-90583-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210806171918.htm

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