Retinoid Metabolism and Signaling in Heart Failure
Vitamin A (retinol), has been studied extensively in coronary heart disease (CHD), as low levels correlate with increased risk of cardiac events in, otherwise, healthy middle-aged men. Like its vegetal precursor, beta-carotene, whose serum levels are also inversely correlated with adverse outcomes, retinol has antioxidant properties, similar to Vitamin E and Vitamin C. Retinol was therefore included in clinical trials, often in combination with b-carotene and/or Vitamins E and C, but ultimately antioxidant trials, with or without retinol, failed to improve patient outcomes.
However, unlike Vitamins E and C, the major cell physiological role of retinol has little to do with direct antioxidant action. Stored primarily in the liver, retinol is a pro-hormone, the body’s source of all-trans retinoic acid (ATRA), a potent transcription-activating hormone present in tissues at nanomolar concentrations. Over 70 years ago it was first shown that the offspring of retinol-deficient rats exhibited structural cardiac defects. The role of ATRA in embryonic cardiac development has, subsequently, been mapped in considerable detail. It is involved in proper cardiac tissue specification, anteroposterior patterning, and endocardial cushion formation, among other processes. Yet, the cellular role of the retinoids, their metabolism, and signaling in adult heart physiology, and HF, remains poorly characterized. Though HF patients do not appear to be retinol-deficient, it is unknown whether ATRA levels are altered. Indeed, the precise relationships between circulating retinol and ATRA levels, cardiac tissue ATRA levels, and intracellular cardiac ATRA signaling, in the context of HF, are unknown.
Our recent work shows that ATRA levels decline nearly 40% in failing human heart tissue. In a guinea pig model, the ATRA decline occurs early in HF progression, and administering ATRA to guinea pigs prevents the onset of HF. We think that low cardiac ATRA attenuates the expression of critical ATRA-dependent gene programs in HF. Getting at the root mechanism underlying ATRA decline might allow us to design an HF therapy based on rebalancing or normalizing ATRA metabolism. To do that, our current focus is on determining which enzymes are principally responsible for the control of ATRA biosynthesis and degradation in the adult mammalian heart.
Yang N, Parker L, Yu J, Jones JW, Liu T, Papanicolaou KN, Talbot CC, Jr., Margulies KB, O’Rourke B, Kane M, and Foster DB. Cardiac retinoic acid levels decline in heart failure. JCI Insight. 2021.