34 research outputs found
Cardiac retinoic acid levels decline in heart failure
Although low circulating levels of the vitamin A metabolite, all-trans retinoic acid (ATRA), are associated with increased risk of cardiovascular events and all-cause mortality, few studies have addressed whether cardiac retinoid levels are altered in the failing heart. Here, we showed that proteomic analyses of human and guinea pig heart failure (HF) were consistent with a decline in resident cardiac ATRA. Quantitation of the retinoids in ventricular myocardium by mass spectrometry revealed 32% and 39% ATRA decreases in guinea pig HF and in patients with idiopathic dilated cardiomyopathy (IDCM), respectively, despite ample reserves of cardiac vitamin A. ATRA (2 mg/kg/d) was sufficient to mitigate cardiac remodeling and prevent functional decline in guinea pig HF. Although cardiac ATRA declined in guinea pig HF and human IDCM, levels of certain retinoid metabolic enzymes diverged. Specifically, high expression of the ATRA-catabolizing enzyme, CYP26A1, in human IDCM could dampen prospects for an ATRA-based therapy. Pertinently, a pan-CYP26 inhibitor, talarozole, blunted the impact of phenylephrine on ATRA decline and hypertrophy in neonatal rat ventricular myocytes. Taken together, we submit that low cardiac ATRA attenuates the expression of critical ATRA-dependent gene programs in HF and that strategies to normalize ATRA metabolism, like CYP26 inhibition, may have therapeutic potential
Integrated Omic Analysis of a Guinea Pig Model of Heart Failure and Sudden Cardiac Death
Here, we examine
key regulatory pathways underlying the transition
from compensated hypertrophy (HYP) to decompensated heart failure
(HF) and sudden cardiac death (SCD) in a guinea pig pressure-overload
model by integrated multiome analysis. Relative protein abundances
from sham-operated HYP and HF hearts were assessed by iTRAQ LC–MS/MS.
Metabolites were quantified by LC–MS/MS or GC–MS. Transcriptome
profiles were obtained using mRNA microarrays. The guinea pig HF proteome
exhibited classic biosignatures of cardiac HYP, left ventricular dysfunction,
fibrosis, inflammation, and extravasation. Fatty acid metabolism,
mitochondrial transcription/translation factors, antioxidant enzymes,
and other mitochondrial procsses, were downregulated in HF but not
HYP. Proteins upregulated in HF implicate extracellular matrix remodeling,
cytoskeletal remodeling, and acute phase inflammation markers. Among
metabolites, acylcarnitines were downregulated in HYP and fatty acids
accumulated in HF. The correlation of transcript and protein changes
in HF was weak (<i>R</i><sup>2</sup> = 0.23), suggesting
post-transcriptional gene regulation in HF. Proteome/metabolome integration
indicated metabolic bottlenecks in fatty acyl-CoA processing by carnitine
palmitoyl transferase (<i>CPT1B</i>) as well as TCA cycle
inhibition. On the basis of these findings, we present a model of
cardiac decompensation involving impaired nuclear integration of Ca<sup>2+</sup> and cyclic nucleotide signals that are coupled to mitochondrial
metabolic and antioxidant defects through the CREB/PGC1α transcriptional
axis