To identify
biological pathways associated with myocardial recovery from
heart failure (HF), gene profiling and gene set enrichment analysis (GSEA) were examined in left ventricle of spontaneously hypertensive rats with HF (SHR-F) with no treatment, following treatment with the
angiotensin converting enzyme inhibitor captopril, and treatment with
captopril combined with the
short chain fatty acid derivative phenylbutyrate. Failing hearts demonstrated depressed left ventricular ejection fraction, while ventricular volume and mass increased.
Captopril treatment alone prevented further deterioration but did not improve myocardial function; relatively few transcripts were differentially expressed relative to untreated SHR-F. Gene sets identified by GSEA as downregulated with
captopril treatment compared to SHR-F group included those related to
hypoxia and
reactive oxygen species, while upregulated gene sets included
G protein signaling. Treatment with phenylbutyrate alone did not improve survival (no animals in this group survived the 30 day treatment period), while phenylbutyrate combined with
captopril increased survival and significantly improved cardiac function in vivo and in vitro. Normalized microarray data identified 780 genes that demonstrated a combined treatment effect of which 258 genes were modified with HF.
Fatty acid metabolism and ion transport were among the most significantly upregulated pathways in the combined treatment group compared to untreated SHR with HF, whereas those related to oxidative stress, growth,
inflammation, protein degradation, and
TGF-beta signaling were downregulated. These findings demonstrate improved myocardial function and regression of
cardiac hypertrophy, and identify many HF related gene sets altered with phenylbutyrate and
captopril treatment, but not
captopril alone. These results characterize gene sets associated with recovery from HF, and suggest that phenylbutyrate may be a potentially effective adjunctive treatment, together with
captopril, by synergistically modulating pathways that contribute to restoration of contractile function of the failing SHR heart.