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MicroRNA-30d regulates cardiomyocyte pyroptosis by directly targeting foxo3a in diabetic cardiomyopathy.

Li X, Du N, Zhang Q, Li J, Chen X, Liu X, Hu Y, Qin W, Shen N, Xu C, Fang Z, Wei Y, Wang R, Du Z, Zhang Y, Lu Y - Cell Death Dis (2014)

Bottom Line: Diabetic cardiomyopathy is a common cardiac condition in patients with diabetes mellitus, which can result in cardiac hypertrophy and subsequent heart failure, associated with pyroptosis, the pro-inflammatory programmed cell death.In an effort to understand the signaling mechanisms underlying the pro-pyroptotic property of mir-30d, we found that forced expression of mir-30d upregulated caspase-1 and pro-inflammatory cytokines IL-1β and IL-18.These findings promoted us to propose a new signaling pathway leading to cardiomyocyte pyroptosis under hyperglycemic conditions: mir-30d↑→foxo3a↓→ ARC↓→caspase-1↑→IL-1β, IL-18↑→pyroptosis↑.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150081, China.

ABSTRACT
Diabetic cardiomyopathy is a common cardiac condition in patients with diabetes mellitus, which can result in cardiac hypertrophy and subsequent heart failure, associated with pyroptosis, the pro-inflammatory programmed cell death. MicroRNAs (miRNAs), small endogenous non-coding RNAs, have been shown to be involved in diabetic cardiomyopathy. However, whether miRNAs regulate pyroptosis in diabetic cardiomyopathy remains unknown. Our study revealed that mir-30d expression was substantially increased in streptozotocin (STZ)-induced diabetic rats and in high-glucose-treated cardiomyocytes as well. Upregulation of mir-30d promoted cardiomyocyte pyroptosis in diabetic cardiomyopathy; conversely, knockdown of mir-30d attenuated it. In an effort to understand the signaling mechanisms underlying the pro-pyroptotic property of mir-30d, we found that forced expression of mir-30d upregulated caspase-1 and pro-inflammatory cytokines IL-1β and IL-18. Moreover, mir-30d directly repressed foxo3a expression and its downstream protein, apoptosis repressor with caspase recruitment domain (ARC). Furthermore, silencing ARC by siRNA mimicked the action of mir-30d: upregulating caspase-1 and inducing pyroptosis. These findings promoted us to propose a new signaling pathway leading to cardiomyocyte pyroptosis under hyperglycemic conditions: mir-30d↑→foxo3a↓→ ARC↓→caspase-1↑→IL-1β, IL-18↑→pyroptosis↑. Therefore, mir-30d may be a promising therapeutic target for the management of diabetic cardiomyopathy.

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The effect of mir-30d on pyroptosis is mediated through downregulation of ARC. (a) ARC levels in the NC, HG+NC and HG+siRNA groups. (b) Immunofluorescence images ( × 400) showing the expression of ARC in cardiomyocytes in the NC, HG+NC and HG+siRNA groups. Blue: nuclear staining (DAPI); green: ARC staining. (c) Caspase-1 protein and mRNA levels in the NC, HG+NC and HG+siRNA groups. (d) Immunofluorescence images ( × 400) showing the expression of caspase-1 in cardiomyocytes in the NC, HG+NC and HG+siRNA groups. Blue: nuclear staining (DAPI); green: caspase-1 staining. (e) IL-1β and IL-18 levels in the NC, HG+NC and HG+siRNA groups. (f) TUNEL (terminal deoxinucleotidyl transferase-mediated dUTP-fluorescein nick end labeling) images showing cell death in the three groups. Blue, nuclear staining (DAPI); green, TUNEL staining; TUNEL nuclear localization in merged image. n=3. *P<0.05 versus NC; #P<0.05 versus HG+NC; mean±S.E.M.
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fig7: The effect of mir-30d on pyroptosis is mediated through downregulation of ARC. (a) ARC levels in the NC, HG+NC and HG+siRNA groups. (b) Immunofluorescence images ( × 400) showing the expression of ARC in cardiomyocytes in the NC, HG+NC and HG+siRNA groups. Blue: nuclear staining (DAPI); green: ARC staining. (c) Caspase-1 protein and mRNA levels in the NC, HG+NC and HG+siRNA groups. (d) Immunofluorescence images ( × 400) showing the expression of caspase-1 in cardiomyocytes in the NC, HG+NC and HG+siRNA groups. Blue: nuclear staining (DAPI); green: caspase-1 staining. (e) IL-1β and IL-18 levels in the NC, HG+NC and HG+siRNA groups. (f) TUNEL (terminal deoxinucleotidyl transferase-mediated dUTP-fluorescein nick end labeling) images showing cell death in the three groups. Blue, nuclear staining (DAPI); green, TUNEL staining; TUNEL nuclear localization in merged image. n=3. *P<0.05 versus NC; #P<0.05 versus HG+NC; mean±S.E.M.

Mentions: It was likely that mir-30d exerted its effect via downregulating ARC. To test this notion, we transfected ARC siRNA into cardiomyocytes under high-glucose conditions. We observed a pronounced elevation of caspase-1 expression. Additionally, ARC knockdown significantly increased caspase-1, IL-1β and IL-18 levels. Gene-specific inhibition of ARC exacerbated high-glucose-induced pyroptosis (Figure 7).


MicroRNA-30d regulates cardiomyocyte pyroptosis by directly targeting foxo3a in diabetic cardiomyopathy.

Li X, Du N, Zhang Q, Li J, Chen X, Liu X, Hu Y, Qin W, Shen N, Xu C, Fang Z, Wei Y, Wang R, Du Z, Zhang Y, Lu Y - Cell Death Dis (2014)

The effect of mir-30d on pyroptosis is mediated through downregulation of ARC. (a) ARC levels in the NC, HG+NC and HG+siRNA groups. (b) Immunofluorescence images ( × 400) showing the expression of ARC in cardiomyocytes in the NC, HG+NC and HG+siRNA groups. Blue: nuclear staining (DAPI); green: ARC staining. (c) Caspase-1 protein and mRNA levels in the NC, HG+NC and HG+siRNA groups. (d) Immunofluorescence images ( × 400) showing the expression of caspase-1 in cardiomyocytes in the NC, HG+NC and HG+siRNA groups. Blue: nuclear staining (DAPI); green: caspase-1 staining. (e) IL-1β and IL-18 levels in the NC, HG+NC and HG+siRNA groups. (f) TUNEL (terminal deoxinucleotidyl transferase-mediated dUTP-fluorescein nick end labeling) images showing cell death in the three groups. Blue, nuclear staining (DAPI); green, TUNEL staining; TUNEL nuclear localization in merged image. n=3. *P<0.05 versus NC; #P<0.05 versus HG+NC; mean±S.E.M.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4237254&req=5

fig7: The effect of mir-30d on pyroptosis is mediated through downregulation of ARC. (a) ARC levels in the NC, HG+NC and HG+siRNA groups. (b) Immunofluorescence images ( × 400) showing the expression of ARC in cardiomyocytes in the NC, HG+NC and HG+siRNA groups. Blue: nuclear staining (DAPI); green: ARC staining. (c) Caspase-1 protein and mRNA levels in the NC, HG+NC and HG+siRNA groups. (d) Immunofluorescence images ( × 400) showing the expression of caspase-1 in cardiomyocytes in the NC, HG+NC and HG+siRNA groups. Blue: nuclear staining (DAPI); green: caspase-1 staining. (e) IL-1β and IL-18 levels in the NC, HG+NC and HG+siRNA groups. (f) TUNEL (terminal deoxinucleotidyl transferase-mediated dUTP-fluorescein nick end labeling) images showing cell death in the three groups. Blue, nuclear staining (DAPI); green, TUNEL staining; TUNEL nuclear localization in merged image. n=3. *P<0.05 versus NC; #P<0.05 versus HG+NC; mean±S.E.M.
Mentions: It was likely that mir-30d exerted its effect via downregulating ARC. To test this notion, we transfected ARC siRNA into cardiomyocytes under high-glucose conditions. We observed a pronounced elevation of caspase-1 expression. Additionally, ARC knockdown significantly increased caspase-1, IL-1β and IL-18 levels. Gene-specific inhibition of ARC exacerbated high-glucose-induced pyroptosis (Figure 7).

Bottom Line: Diabetic cardiomyopathy is a common cardiac condition in patients with diabetes mellitus, which can result in cardiac hypertrophy and subsequent heart failure, associated with pyroptosis, the pro-inflammatory programmed cell death.In an effort to understand the signaling mechanisms underlying the pro-pyroptotic property of mir-30d, we found that forced expression of mir-30d upregulated caspase-1 and pro-inflammatory cytokines IL-1β and IL-18.These findings promoted us to propose a new signaling pathway leading to cardiomyocyte pyroptosis under hyperglycemic conditions: mir-30d↑→foxo3a↓→ ARC↓→caspase-1↑→IL-1β, IL-18↑→pyroptosis↑.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin 150081, China.

ABSTRACT
Diabetic cardiomyopathy is a common cardiac condition in patients with diabetes mellitus, which can result in cardiac hypertrophy and subsequent heart failure, associated with pyroptosis, the pro-inflammatory programmed cell death. MicroRNAs (miRNAs), small endogenous non-coding RNAs, have been shown to be involved in diabetic cardiomyopathy. However, whether miRNAs regulate pyroptosis in diabetic cardiomyopathy remains unknown. Our study revealed that mir-30d expression was substantially increased in streptozotocin (STZ)-induced diabetic rats and in high-glucose-treated cardiomyocytes as well. Upregulation of mir-30d promoted cardiomyocyte pyroptosis in diabetic cardiomyopathy; conversely, knockdown of mir-30d attenuated it. In an effort to understand the signaling mechanisms underlying the pro-pyroptotic property of mir-30d, we found that forced expression of mir-30d upregulated caspase-1 and pro-inflammatory cytokines IL-1β and IL-18. Moreover, mir-30d directly repressed foxo3a expression and its downstream protein, apoptosis repressor with caspase recruitment domain (ARC). Furthermore, silencing ARC by siRNA mimicked the action of mir-30d: upregulating caspase-1 and inducing pyroptosis. These findings promoted us to propose a new signaling pathway leading to cardiomyocyte pyroptosis under hyperglycemic conditions: mir-30d↑→foxo3a↓→ ARC↓→caspase-1↑→IL-1β, IL-18↑→pyroptosis↑. Therefore, mir-30d may be a promising therapeutic target for the management of diabetic cardiomyopathy.

Show MeSH
Related in: MedlinePlus