Attenuation of beta2-adrenergic receptors and homocysteine metabolic enzymes cause diabetic cardiomyopathy

Mishra, Paras Kumar; Givvimani, Srikanth; Metreveli, Naira; Tyagi, Suresh C.

doi:10.1016/j.bbrc.2010.09.006

Cited by 29 publications

(34 citation statements)

References 30 publications

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“…Hcy is reported to play crucial role in pathological cardiac remodeling [2, 3, 5, 18, 32–34]. However, there is debate on whether Hcy is a cause or effect of cardiovascular diseases [27].…”

Section: Discussionmentioning

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: 99%

“…They are recognized as a novel therapeutic target for cardiovascular diseases [18, 19]. In human hearts, >800 miRNAs are present and >250 miRNAs are differentially regulated in pathological hearts [20].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“…DCM results in cardiac functional and structural changes, independent of hypertension, coronary artery disease, or any other known cardiac disease. The structural changes include fibrosis, apoptosis, hypertrophy of myocytes and the functional changes include systolic and diastolic dysfunction [2][3][4][5][6][7]. DCM patients do not show special clinical symptoms in the early stage which makes it difficult for early clinical diagnosis and effective treatment.…”

Section: Introductionmentioning

confidence: 98%

Advanced Interfere Treatment of Diabetic Cardiomyopathy Rats by aFGF-Loaded Heparin-Modified Microbubbles and UTMD Technique

Zhang

Shen³

et al. 2016

Cardiovasc Drugs Ther

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This study aims to investigate the preclinical performance and mechanism of a novel strategy of aFGF-loaded heparin-modified microbubbles (aFGF-HMB) combined with ultrasound-targeted microbubble destruction (UTMD) technique for diabetic cardiomyopathy (DCM) prevention. Type 1 diabetic rats were induced by streptozotocin. Twelve weeks after intervention, indexes from transthoracic echocardiography and cardiac catheterization showed that the left ventricular function in the aFGF-HMB/UTMD group was significantly improved compared with diabetes control (DM). From Picrosirius Red staining and TUNEL staining, the aFGF-HMB/UTMD group showed significant difference from the other groups. The cardiac collagen volume fraction (CVF) and myocardial cell apoptosis index (AI) in aFGF-HMB/UTMD group decreased to 7.2 % and 7.11 % respectively, compared with the DM group (CVF = 24.5 % and AI =20.3 % respectively). The results of myocardial microvascular density (MCD) also proved the strongest inhibition of aFGF-HMB/UTMD group on DCM progress. CD31 staining of aFGF-HMB/UTMD group reached 22 n/hrp, much higher than that of DM group (9 n/hrp). These results confirmed that the abnormalities including left ventricular dysfunction, myocardial fibrosis, cardiomyocytes apoptosis and microvascular rarefaction could be suppressed by twice weekly aFGF treatments for 12 consecutive weeks (free aFGF or aFGF-HMB+/-UTMD), with the strongest improvements observed in the aFGF-HMB/UTMD group (P < 0.05 vs free aFGF or aFGF-HMB). Western blot analyses of heart tissue further revealed the highest aFGF, anti-apoptosis protein (Bcl-2), VEGF-C, pAkt, pFoxo-3a levels and strongest reduction in pro-apoptosis proteins (Bax) level in aFGF-HMB/UTMD group. Overall, aFGF-HMB combined with UTMD technique might be developed as an effective strategy to prevent DCM in future clinical therapy.

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“…MicroRNAs are tiny (~22 nt), conserved, non-coding RNAs that modulate gene expression both at mRNA and post-transcriptional levels by either degrading mRNA (if seed sequence match perfectly with mRNA) or inhibiting translation (if seed sequence have incomplete complimentarity [19;20]. In the heart, attenuation of miR-133a causes hypertrophy [4], fibrosis [18] and arrhythmia [31] making it a crucial miRNA involved in the heart failure.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-133a regulates DNA methylation in diabetic cardiomyocytes

Chavali¹,

Tyagi²,

Mishra³

2012

Biochemical and Biophysical Research Communications

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We tested the hypothesis that miR-133a regulates DNA methylation by inhibiting Dnmt-1 (maintenance) and Dnmt-3a and -3b (de novo) methyl transferase in diabetic hearts by using Ins2+/− Akita (diabetic) and C57BL/6J (WT) mice and HL1 cardiomyocytes. The specific role of miR-133a in DNA methylation in diabetes was assessed by two treatment groups (1) scrambled, miR-133a mimic, anti-miR-133a, and (2) 5mM glucose (CT), 25mM glucose (HG) and HG+miR-133a mimic. The levels of miR-133a, Dnmt-1, -3a and -3b were measured by multiplex RT-PCR, qPCR and Western blotting. The results revealed that miR-133a is inhibited but Dnmt-1 and -3b are induced in Akita suggesting that attenuation of miR-133a induces both maintenance (Dnmt-1) - and de-novo -methylation (Dnmt-3b) in diabetes. The up regulation of Dnmt-3a elicits intricate and antagonizing interaction between Dnmt-3a and -3b. In cardiomyocytes, over expression of miR-133a inhibits but silencing of miR-133a induces Dnmt-1, -3a and -3b elucidating the involvement of miR-133a in regulation of DNA methylation. The HG treatment up regulates only Dnmt-1 and not Dnmt-3a and -3b suggesting that acute hyperglycemia triggers only maintenance methylation. The over expression of miR-133a mitigates glucose mediated induction of Dnmt-1 elucidating the role of miR-133a in regulation of DNA methylation in diabetes.

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Attenuation of beta2-adrenergic receptors and homocysteine metabolic enzymes cause diabetic cardiomyopathy

Cited by 29 publications

References 30 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

Advanced Interfere Treatment of Diabetic Cardiomyopathy Rats by aFGF-Loaded Heparin-Modified Microbubbles and UTMD Technique

MicroRNA-133a regulates DNA methylation in diabetic cardiomyocytes

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