ABSTRACT
Introduction: MicroRNAs (miRs) are small noncoding RNAs which are regulators of gene expression and also regulate the genes in heart tissues. The aim of the study was to evaluate the effect of miRs on the expression level of myosin heavy chain (MHC), which is responsible for regulation of cardiac functions in neonatal rat ventricular myocytes and mice. Material and methods: The miRs were suppressed in neonatal rat ventricular myocytes using small interfering RNAs (siRNAs) against Dicer followed by evaluation of MHC levels. For in vivo study the C57 black/6 Jacksonian mice were subjected to the transverse aortic constriction (TAC) procedure. Results: The Dicer siRNA suppressed the endogenous miRs and the α-MHC gene but failed to down-regulate the ß-MHC. Among the 17 selected miRs, miR-29a was found to up-regulate the α-MHC gene significantly but not ß-MHC. The expression of α-MHC was suppressed by silencing the expression of miR-29a. Bioinformatics study done by TargetScan suggested thyroid hormone receptor-ß1 (TR-ß1) as a potential target of miR-29a. Additionally, miR-29a was found to regulate the expression of α-MHC via TR-ß1 signaling. Conclusions: The findings of the present study indicated that miR-29a modulates expression of α-the MHC gene by targeting TR-ß1 in cardiac cells. The study may provide a new direction for treating cardiac failure and cardiac hypertrophy.
ABSTRACT
Neuroserpin, the major inhibitor of tissue plasminogen activator (tPA) in brain, has been shown to be up-regulated in Alzheimer's disease (AD). Inhibition of tPA activity leads to reduced brain levels of plasmin, one of the main enzymes responsible for the degradation and clearance of amyloid-beta and its plaques from the brain. Thyroid hormone is one of the few factors known to enhance expression of neuroserpin in neurons. Thyroid hormone acts on neurons by binding to its receptors THR1α and THR1ß, which then function in the nucleus to up-regulate the expression of numerous genes including the RNA-binding protein HuD. HuD acts post-transcriptionally to enhance expression of numerous proteins including neuroserpin by stabilizing their mRNAs. A series of Alzheimer's disease brain tissues were compared to age-matched control brains for their expression of neuroserpin, THRß1 and HuD by western blotting. Alzheimer's disease brain tissues with elevated neuroserpin protein also showed increased expression of THRß1 and HuD. Pair-wise analyses showed significant correlation p-values between neuroserpin, THRß1 and HuD levels; suggesting that the up-regulation of neuroserpin in Alzheimer's disease brain may result from an activation of the thyroid hormone response system in these individuals. These findings provide evidence for a potential relationship between thyroid hormone disorders and Alzheimer's disease.