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Cardiac retinoic acid levels decline in heart failure
Ni Yang, … , Maureen A. Kane, D. Brian Foster
Ni Yang, … , Maureen A. Kane, D. Brian Foster
Published March 16, 2021
Citation Information: JCI Insight. 2021;6(8):e137593. https://doi.org/10.1172/jci.insight.137593.
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Research Article Cardiology

Cardiac retinoic acid levels decline in heart failure

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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.

Authors

Ni Yang, Lauren E. Parker, Jianshi Yu, Jace W. Jones, Ting Liu, Kyriakos N. Papanicolaou, C. Conover Talbot Jr., Kenneth B. Margulies, Brian O’Rourke, Maureen A. Kane, D. Brian Foster

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Figure 6

Remodeling of the enzymes of ATRA metabolism differs between guinea pig and human heart failure.

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Remodeling of the enzymes of ATRA metabolism differs between guinea pig ...
(A) Guinea pig HF: Groups are as defined in Figure 3. N values are given in parentheses. ALDH1A1 protein levels followed a trend of progressive downregulation in HF that differed significantly from Ctrl at 2 weeks and 4 weeks. LIMMA-moderated t test as in ref. 21; §: P < 0.001, ¥: P < 0.01. Transcript levels of CYP26A1 fell significantly by 4-week HF, whereas levels of CYP26B1 and CYP26C1 were unchanged (1-way ANOVA, post hoc Tukey’s HSD; *: P < 0.05). (B) Human IDCM: immunoblot signal intensities were analyzed as detailed in Methods. Group mean differences were assessed by a 2-tailed t test (#: P < 0.0001). Immunoblots indicate that retinaldehyde dehydrogenase 1 (ALDH1A1) was expressed at low levels in the myocardium of healthy donors but was increased approximately 10-fold in patients with IDCM. CYP26A1 levels were highly variable and substantially upregulated in IDCM. CYP26B1 was only detected marginally and not quantified. CYP26C1 was detected in human hearts, but levels did not differ significantly between donors and patients.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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