Cardiac retinoic acid levels decline in heart failure

JCI Insight. 2021 Apr 22;6(8):e137593. doi: 10.1172/jci.insight.137593.

Abstract

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.

Keywords: Cardiology; Heart failure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Animals, Newborn
  • Benzothiazoles / pharmacology
  • Cardiomyopathy, Dilated / metabolism*
  • Cytochrome P-450 Enzyme Inhibitors / pharmacology
  • Cytochrome P450 Family 26 / antagonists & inhibitors
  • Female
  • Gene Expression Regulation
  • Guinea Pigs
  • Heart Failure / metabolism*
  • Heart Ventricles / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Myocardium / metabolism*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Rats
  • Tretinoin / metabolism*
  • Tretinoin / pharmacology
  • Triazoles / pharmacology
  • Ventricular Remodeling / drug effects
  • Vitamin A / metabolism*
  • Young Adult

Substances

  • Benzothiazoles
  • Cytochrome P-450 Enzyme Inhibitors
  • Triazoles
  • Vitamin A
  • Tretinoin
  • Cytochrome P450 Family 26
  • R 115866