Ramipril modulates circadian gene expression in skeletal muscle

Abstract

Treatment with angiotensin converting enzyme (ACE)-inhibitors favorably affects glucose metabolism and the development of diabetes mellitus by largely elusive mechanisms. To identify these mechanisms, we studied the effect of ACE-inhibition on gene expression in skeletal muscle, a primary target tissue for insulin in glucose homeostasis. A subject-blinded and analyst-blinded, placebo-controlled study was conducted in nine healthy men. Two consecutive muscle biopsies were conducted before and 9 h after a single dose of either 10-mg ramipril (n=6) or placebo (n=3), (randomly allocated). Muscle ribonucleic acid was subjected to transcriptome profiling. In both ramipril-treated or placebo-treated individuals, the majority of genes with differential expression between the two time points belonged to the family of diurnally regulated genes, such as the NR1D1 and NR1D2 genes (nuclear receptor subfamily 1, group D, members 1 and 2) or members of the period homolog family (PER1-3). Ramipril significantly modulated the expression of other diurnally regulated genes, such as aryl hydrocarbon receptor nuclear translocator-like (ARNTL), encoding aryl hydrocarbon receptor nuclear translocator-like, a core component of the circadian clock (P=0.02). Concomitant attenuation of NR1D1 downregulation (-2.4-fold compared with -4.1-fold in placebo; P=0.04), a transcriptional repressor of ARNTL, supported the view that ramipril might modulate glucose homeostasis pathways involving the NR1D1 ARNTL axis. As circadian rhythms are deranged in patients who are diabetic, modulated expression of circadian clock genes by ramipril could explain the favorable metabolic effects of therapeutic ACE-inhibition.