Thyroid hormone affects diabetes‐induced changes on cardiac myosin heavy chain gene expression

Abstract

Ventricular muscle expresses two isoforms of myosin heavy chain (MHC) genes: beta and alpha; which are arranged in tandem on the chromosome. Endogenous mRNA of beta and alpha MHCs are expressed in an antithetical manner in control, diabetic, hypo‐ and hyperthyroid rat hearts. We have identified an intergenic region between the beta and alpha genes that modulates the transcription of alpha sense and beta antisense pre‐mRNAs, we believe the intergenic bidirectional promoter controls the antithetic expression of alpha and beta MHC genes. The alpha MHC gene is predominantly expressed in adult rat heart. However, in the diabetic state, the expression of alpha is decreased and beta is increased. Thyroid hormone treatment has been shown to have a large impact on cardiac MHC gene expression and is a positive regulator of alpha MHC and negative regulator of the beta MHC gene. The pathways that regulate MHC isoform expression are unclear. By examining the sequence of beta sense, beta antisense and alpha sense promoters, we hopefully can discern the factors that alter the MHC expression in response to diabetes and thyroid hormone. We attempt to "rescue" diabetic (STZ treated) adult and neonatal rats using low levels of thyroid hormone; and show an effective response on MHC isoform expression and antisense and sense promoter activity. Supported by Amer. Diabetes Assoc and NIHHL.