Differential Expression of Dicer, miRNAs, and Inflammatory Markers in Diabetic Ins2+/− Akita Hearts

Chavali, Vishalakshi; Tyagi, Suresh C.; Mishra, Paras Kumar

doi:10.1007/s12013-013-9679-4

Cited by 82 publications

(95 citation statements)

References 78 publications

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“…HHcy inactivates and down regulates MEF2C in the cardiomyocytes (Figure 3A–C). Since miR-133a is attenuated in the failing human hearts [24] and in diabetic hearts [22, 28], and its role is established as anti-hypertrophy [24, 39] and anti-fibrosis [22, 23], our results suggest a new role of Hcy in miR-133a mediated pathological remodeling in the heart, which is relevant to the human heart failure.…”

Section: Discussionmentioning

confidence: 88%

“…The miRNA Reverse Transcriptase-PCR followed by Taqman qPCR were performed using miR-133a (Assay ID-002246) and U6 SnRNA (Assay ID: 001973) specific primers following the manufacturer’s instruction and protocol (Life technologies, USA). The details of the protocol is published elsewhere [28]. U6 SnRNA was used as an endogenous control for miR-133a.…”

Section: Methodsmentioning

confidence: 99%

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Hydrogen sulfide mitigates homocysteine-mediated pathological remodeling by inducing miR-133a in cardiomyocytes

et al. 2015

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An elevated level of homocysteine called hyperhomocysteinemia (HHcy) is associated with pathological cardiac remodeling. Hydrogen sulfide (H2S) acts as a cardioprotective gas, however the mechanism by which H2S mitigates homocysteine mediated pathological remodeling in cardiomyocytes is unclear. We hypothesized that H2S ameliorates HHcy mediated hypertrophy by inducing cardioprotective miR-133a in cardiomyocytes. To test the hypothesis, HL1 cardiomyocytes were treated with: 1) plain medium (control, CT), 2) 100μM of homocysteine (Hcy), 3) Hcy with 30μM of H2S (Hcy+H2S), and 4) H2S for 24 hour. The levels of hypertrophy markers: c-fos, atrial natriuretic peptide (ANP), and beta-myosin heavy chain (β-MHC), miR-133a and its transcriptional inducer myosin enhancer factor- 2c (MEF2C) were determined by Western blotting, RT-qPCR, and immunofluorescence. The activity of MEF2C was assessed by co-immunoprecipitation of MEF2C with histone deacetylase -1(HDAC1). Our results show that H2S ameliorates homocysteine mediated up regulation of c-fos, ANP and β-MHC, and down regulation of MEF2C and miR-133a. HHcy induces the binding of MEF2C with HDAC1, whereas H2S releases MEF2C from MEF2C-HDAC1 complex causing activation of MEF2C. These findings elicit that HHcy induces cardiac hypertrophy by promoting MEF2C-HDAC1 complex formation that inactivates MEF2C causing suppression of anti-hypertrophy miR-133a in cardiomyocytes. H2S mitigates hypertrophy by inducing miR-133a through activation of MEF2C in HHcy cardiomyocytes. To our knowledge this is a novel mechanism of H2S mediated activation of MEF2C and induction of miR-133a and inhibition of hypertrophy in HHcy cardiomyocytes.

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Section: Discussionmentioning

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Hydrogen sulfide mitigates homocysteine-mediated pathological remodeling by inducing miR-133a in cardiomyocytes

et al. 2015

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“…Previous studies have shown that miR-133a has a role in the contractility of the pressure-overload heart (27) and that miR-133a is downregulated in diabetic hearts (28). To determine whether the lack of miR-133a decreased the contractility of the diabetic heart, we overexpressed miR-133a in the diabetic hearts by miR-133a mimic treatment and validated the upregulated miR-133a in the diabetic hearts by individual miR-133a assay (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Lack of miR-133a Decreases Contractility of Diabetic Hearts: A Role for Novel Cross Talk Between Tyrosine Aminotransferase and Tyrosine Hydroxylase

et al. 2016

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MicroRNAs (miRNAs) have a fundamental role in diabetic heart failure. The cardioprotective miRNA-133a (miR-133a) is downregulated, and contractility is decreased in diabetic hearts. Norepinephrine (NE) is a key catecholamine that stimulates contractility by activating β-adrenergic receptors (β-AR). NE is synthesized from tyrosine by the rate-limiting enzyme, tyrosine hydroxylase (TH), and tyrosine is catabolized by tyrosine aminotransferase (TAT). However, the cross talk/link between TAT and TH in the heart is unclear. To determine whether miR-133a plays a role in the cross talk between TH and TAT and regulates contractility by influencing NE biosynthesis and/or β-AR levels in diabetic hearts, Sprague-Dawley rats and miR-133a transgenic (miR-133aTg) mice were injected with streptozotocin to induce diabetes. The diabetic rats were then treated with miR-133a mimic or scrambled miRNA. Our results revealed that miR-133a mimic treatment improved the contractility of the diabetic rat’s heart concomitant with upregulation of TH, cardiac NE, β-AR, and downregulation of TAT and plasma levels of NE. In miR-133aTg mice, cardiac-specific miR-133a overexpression prevented upregulation of TAT and suppression of TH in the heart after streptozotocin was administered. Moreover, miR-133a overexpression in CATH.a neuronal cells suppressed TAT with concomitant upregulation of TH, whereas knockdown and overexpression of TAT demonstrated that TAT inhibited TH. Luciferase reporter assay confirmed that miR-133a targets TAT. In conclusion, miR-133a controls the contractility of diabetic hearts by targeting TAT, regulating NE biosynthesis, and consequently, β-AR and cardiac function.

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“…↑ Increased (Nielsen et al 2002, Ueno et al 2008, Pulinilkunnil et al 2013, Kuramoto et al 2014, Yan et al 2015, Novgorodov et al 2016 ↑ Increased (Bugger et al 2008, Basu et al 2009, Pulinilkunnil et al 2013 Glucose oxidation ↓ Decreased (Pulinilkunnil et al 2013) ↓ Decreased (Bugger et al 2008, Basu et al 2009) Fatty acid oxidation ↑ Increased (Pulinilkunnil et al 2013) ↑ Increased (Bugger et al 2008, Basu et al 2009) Pathways modulated Inflammation ↑ Increased (Westermann et al 2009) ↑ Increased (Wang et al 2013) ↑ Increased (Chavali et al 2014) Mitochondrial function Dysfunction/abnormal (Pulinilkunnil et al 2013, Xu et al 2013, Novgorodov et al 2016 Dysfunction/abnormal (Shen et al 2004, Ye et al 2004, Xie et al 2011, Vadvalkar et al 2013, Xu et al 2013 Dysfunction/abnormal (Bugger et al 2008(Bugger et al , 2009 (Continued) R233 Review r h ritchie and others Lipid metabolism and diabetic cardiomyopathy impaired folding of proinsulin leading to endoplasmic reticulum (ER) stress in pancreatic islets such that Akita mice exhibit progressive loss of beta-cells, which correlates with diabetes development. Hyperglycaemia is evident from 3 to 4 weeks of age.…”

Section: ) Cardiac Lipidsmentioning

confidence: 99%

Lipid metabolism and its implications for type 1 diabetes-associated cardiomyopathy

Ritchie

Zerenturk

Prakoso

et al. 2017

Journal of Molecular Endocrinology

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Diabetic cardiomyopathy was first defined over four decades ago. It was observed in small post-mortem studies of diabetic patients who suffered from concomitant heart failure despite the absence of hypertension, coronary disease or other likely causal factors, as well as in large population studies such as the Framingham Heart Study. Subsequent studies continue to demonstrate an increased incidence of heart failure in the setting of diabetes independent of established risk factors, suggesting direct effects of diabetes on the myocardium. Impairments in glucose metabolism and handling receive the majority of the blame. The role of concomitant impairments in lipid handling, particularly at the level of the myocardium, has however received much less attention. Cardiac lipid accumulation commonly occurs in the setting of type 2 diabetes and has been suggested to play a direct causal role in the development of cardiomyopathy and heart failure in a process termed as cardiac lipotoxicity. Excess lipids promote numerous pathological processes linked to the development of cardiomyopathy, including mitochondrial dysfunction and inflammation. Although somewhat underappreciated, cardiac lipotoxicity also occurs in the setting of type 1 diabetes. This phenomenon is, however, largely understudied in comparison to hyperglycaemia, which has been widely studied in this context. The current review addresses the changes in lipid metabolism occurring in the type 1 diabetic heart and how they are implicated in disease progression. Furthermore, the pathological pathways linked to cardiac lipotoxicity are discussed. Finally, we consider novel approaches for modulating lipid metabolism as a cardioprotective mechanism against cardiomyopathy and heart failure.

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Differential Expression of Dicer, miRNAs, and Inflammatory Markers in Diabetic Ins2+/− Akita Hearts

Cited by 82 publications

References 78 publications

Hydrogen sulfide mitigates homocysteine-mediated pathological remodeling by inducing miR-133a in cardiomyocytes

Hydrogen sulfide mitigates homocysteine-mediated pathological remodeling by inducing miR-133a in cardiomyocytes

Lack of miR-133a Decreases Contractility of Diabetic Hearts: A Role for Novel Cross Talk Between Tyrosine Aminotransferase and Tyrosine Hydroxylase

Lipid metabolism and its implications for type 1 diabetes-associated cardiomyopathy

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