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Cardiac‐specific Overexpression of MiR‐133a Decreases Pyroptosis in Ins2 +/− T1DM Mice Heart
Author(s) -
Kambis Tyler N.,
Yadav Santosh K.,
Mishra Paras K.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.838.12
Subject(s) - pyroptosis , downregulation and upregulation , caspase 1 , inflammasome , programmed cell death , medicine , endocrinology , biology , apoptosis , andrology , inflammation , gene , biochemistry
Increased pyroptosis (a caspase‐1‐dependent cell death) and decreased miR‐133a (the most abundant cardioprotective miRNA in the human heart) are documented in the diabetic mellitus (DM) heart. However, it is unclear whether the reduced miR‐133a in DM hearts induces cardiac pyroptosis. We hypothesized that lack of miR‐133a in the diabetic heart induces pyroptosis, which is suppressed by the overexpression of miR‐133a. To test the hypothesis, we created a novel diabetic mice strain where miR‐133a is overexpressed only in the heart (Akita/miR‐133aTg), by crossbreeding Ins2 +/− Akita (spontaneous, genetic T1DM) male with cardiac‐specific miR‐133a transgenic (miR‐133aTg) female mice. We have used sibling Ins2 +/+ mice as WT for Ins2 +/− Akita mice. In the four groups (WT, Akita, Akita/miR‐133aTg and miR‐133aTg) of fourteen‐week male mice, we measured the levels of pyroptosis markers NLRP3 (involved in the inflammasome complex formation that is required for pyroptosis initiation), caspase‐1 (the key enzyme for pyroptosis), and interleukine‐1β (IL‐1β) (a pro‐inflammatory cytokine that is involved in pyroptosis) in the heart. The densitometric analyses of Western blots revealed that protein levels of pyroptosis markers are upregulated in Akita hearts, whereas the overexpression of miR‐133a blunts this upregulation. The protein expression of different pyroptosis markers in the above‐mentioned four groups of hearts were; NLRP3 : WT 0.04 ± 0.0, Akita 0.09 ± 0.1, Akita/miR‐133aTg 0.03 ± 0.0, miR‐133aTg 0.01 ± 0.0; caspase 1 : WT 0.7 ± 0.1, Akita 1.0 ± 0.1, Akita/miR‐133aTg 0.2 ± 0.0, miR‐133aTg 0.1 ± 0.0, and IL‐1β : WT 1.9 ± 0.6, Akita 2.1 ± 0.3, Akita/miR‐133aTg 1.1 ± 0.0, miR‐133aTg 0.8 ± 0.1 (the standard deviation values are rounded to one decimal point). In conclusion, this is the first report showing that cardiac‐specific overexpression of miR‐133a mitigates DM‐induced pyroptosis in the heart. Support or Funding Information Department of Cellular and Integrative Physiology, University of Nebraska Medical Center This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .