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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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Cardiac function in STZ-induced diabetic rats. (a) Body weight and fasting blood glucose levels measured at 4 weeks after STZ injection in the control and DM groups. (b) Body weight and blood glucose levels during the last week before rats were anesthetized. n=5. (c) Echocardiogram and ejection fraction (EF %) and fractional shortening (FS %) measurements of control and DM rats at the end of the fourth week before rats were anesthetized. n=3. (d) HE staining and Masson staining of cross-sectional tissue slices of heart tissue in the control and DM groups ( × 200). Scale bar: 20 μm. n=4. (e) Areas of myocyte and fibrosis in control and DM rats. n=5. (f) Transmission electron microscopy micrograph results in the control and DM groups ( × 10 000). n=3. *P<0.05 & **P<0.01 versus control; mean±S.E.M.
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fig1: Cardiac function in STZ-induced diabetic rats. (a) Body weight and fasting blood glucose levels measured at 4 weeks after STZ injection in the control and DM groups. (b) Body weight and blood glucose levels during the last week before rats were anesthetized. n=5. (c) Echocardiogram and ejection fraction (EF %) and fractional shortening (FS %) measurements of control and DM rats at the end of the fourth week before rats were anesthetized. n=3. (d) HE staining and Masson staining of cross-sectional tissue slices of heart tissue in the control and DM groups ( × 200). Scale bar: 20 μm. n=4. (e) Areas of myocyte and fibrosis in control and DM rats. n=5. (f) Transmission electron microscopy micrograph results in the control and DM groups ( × 10 000). n=3. *P<0.05 & **P<0.01 versus control; mean±S.E.M.

Mentions: To study diabetic cardiomyopathy, we first developed a rat model of diabetes mellitus (DM) induced by STZ and high-fat diet.22,23 As shown in Figures 1a and b, DM rats showed significant increases in fasting blood glucose levels, blood triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL) and water intake, accompanied by decreases in body weight and high-density lipoprotein (HDL) (Supplementary Table S1). These results indicated the DM rats had typical diabetic phenotypes, including hyperglycemia and hyperlipidemia.


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)

Cardiac function in STZ-induced diabetic rats. (a) Body weight and fasting blood glucose levels measured at 4 weeks after STZ injection in the control and DM groups. (b) Body weight and blood glucose levels during the last week before rats were anesthetized. n=5. (c) Echocardiogram and ejection fraction (EF %) and fractional shortening (FS %) measurements of control and DM rats at the end of the fourth week before rats were anesthetized. n=3. (d) HE staining and Masson staining of cross-sectional tissue slices of heart tissue in the control and DM groups ( × 200). Scale bar: 20 μm. n=4. (e) Areas of myocyte and fibrosis in control and DM rats. n=5. (f) Transmission electron microscopy micrograph results in the control and DM groups ( × 10 000). n=3. *P<0.05 & **P<0.01 versus control; 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

fig1: Cardiac function in STZ-induced diabetic rats. (a) Body weight and fasting blood glucose levels measured at 4 weeks after STZ injection in the control and DM groups. (b) Body weight and blood glucose levels during the last week before rats were anesthetized. n=5. (c) Echocardiogram and ejection fraction (EF %) and fractional shortening (FS %) measurements of control and DM rats at the end of the fourth week before rats were anesthetized. n=3. (d) HE staining and Masson staining of cross-sectional tissue slices of heart tissue in the control and DM groups ( × 200). Scale bar: 20 μm. n=4. (e) Areas of myocyte and fibrosis in control and DM rats. n=5. (f) Transmission electron microscopy micrograph results in the control and DM groups ( × 10 000). n=3. *P<0.05 & **P<0.01 versus control; mean±S.E.M.
Mentions: To study diabetic cardiomyopathy, we first developed a rat model of diabetes mellitus (DM) induced by STZ and high-fat diet.22,23 As shown in Figures 1a and b, DM rats showed significant increases in fasting blood glucose levels, blood triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL) and water intake, accompanied by decreases in body weight and high-density lipoprotein (HDL) (Supplementary Table S1). These results indicated the DM rats had typical diabetic phenotypes, including hyperglycemia and hyperlipidemia.

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