ACE-inhibition induces a cardioprotective transcriptional response in the metabolic syndrome heart

TLDR

Metabolic syndrome-associated cardiovascular disease is common, yet its underlying cardiomyopathy mechanisms remain poorly understood. The study aimed to characterize the cardiac transcriptome of a murine metabolic syndrome model versus healthy controls and to assess transcriptional changes induced by ACE‑inhibition. RNA‑seq and differential expression analysis were performed on DKO and WT hearts to identify ACE‑inhibition–induced transcriptional changes. RNA‑seq identified 288 differentially expressed genes between DKO and WT hearts across 72 pathways, revealing metabolic cardiomyopathy hallmarks such as heightened integrin‑linked kinase, Rho, and oxidative‑stress signaling, while ACE‑inhibition modestly altered WT gene expression (55 genes) but profoundly affected DKO hearts (1,143 genes, 104 pathways), counteracting MetS‑specific pathways and activating cardioprotective mechanisms, demonstrating distinct transcriptional profiles and a partially specific ACE‑inhibition response.

Abstract

Abstract Cardiovascular disease associated with metabolic syndrome has a high prevalence, but the mechanistic basis of metabolic cardiomyopathy remains poorly understood. We characterised the cardiac transcriptome in a murine metabolic syndrome (MetS) model (LDLR−/−; ob/ob, DKO) relative to the healthy, control heart (C57BL/6, WT) and the transcriptional changes induced by ACE-inhibition in those hearts. RNA-Seq, differential gene expression and transcription factor analysis identified 288 genes differentially expressed between DKO and WT hearts implicating 72 pathways. Hallmarks of metabolic cardiomyopathy were increased activity in integrin-linked kinase signalling, Rho signalling, dendritic cell maturation, production of nitric oxide and reactive oxygen species in macrophages, atherosclerosis, LXR-RXR signalling, cardiac hypertrophy, and acute phase response pathways. ACE-inhibition had a limited effect on gene expression in WT (55 genes, 23 pathways), and a prominent effect in DKO hearts (1143 genes, 104 pathways). In DKO hearts, ACE-I appears to counteract some of the MetS-specific pathways, while also activating cardioprotective mechanisms. We conclude that MetS and control murine hearts have unique transcriptional profiles and exhibit a partially specific transcriptional response to ACE-inhibition.