Cardiac Lysine Acetylation
Acetylation of lysine residues on histones was first recognized as a post-translational modification nearly 50 years ago. In the years since, families of histone acetyltransferases and deacetylases have been discovered, and nuclear protein acetylation has emerged as paramount in chromatin remodeling and transcriptional regulation. In the heart, histone acetylation is a mediator of the transcriptional programs that underlie cardiomyocyte proliferation, differentiation, and cardiac remodeling in pathological hypertrophy.
Over the last decade, preoteomic studies have indicated that lysine acetylation extends beyond the nucleus. It has become apparent that lysine acetylation is a widespread, evolutionarily conserved post-translational modification whose scope rivals phosphorylation. Studies have shown that caloric restriction in mice is cardioprotective and leads to diminished acetylation of mitochondrial proteins, which in turn, correlates with reduced ROS production from the electron transport chain.
Given the emerging prominence of extra-nuclear lysine acetylation, we undertook a proteomic approach to characterize the broader lysine acetylome of guinea pig hearts. We found that in addition to nuclear and mitochondrial proteins, proteins of the excitation-contraction coupling axis are, likewise acetylated. Including Ca2+-handling proteins, RyR2 and SERCA2, and myofilament proteins such as myosin actin and troponin complex. In collaboration with Dr. Anthony Cammarato (Johns Hopkins) and Brandon Biesiadecki (Ohio State) we are probing thin filament acetylation dynamics in heart failure and its impact on myofilament function.
Foster DB, Liu T, Rucker J, O’Meally RN, Devine LR, Cole RN, and O’Rourke B. The cardiac acetyl-lysine proteome. PLoS ONE. 2013. 8(7): p. e67513
Lin YH, Schmidt W, Fritz KS, Jeong MY, Cammarato A, Foster DB, Biesiadecki BJ, McKinsey TA, and Woulfe KC. Site-specific acetyl-mimetic modification of cardiac troponin i modulates myofilament relaxation and calcium sensitivity. J Mol Cell Cardiol. 2020. 139: p. 135-147.
Schmidt W, Madan A, Foster DB, and Cammarato A. Lysine acetylation of F-actin decreases tropomyosin-based inhibition of actomyosin activity. J Biol Chem. 2020. 295(46): p. 15527-15539
My lab maintains a strong interest, and active fruitful collaborations, in the field of cardiac myofilament structure/function and how it is perturbed in heart disease ranging from myocardial stunning to hypertrophic cardiomyopathy and heart failure. Collaborators include Dr. Anne Murphy, Dr. Jolanda van der Velden, Dr. Ger Stienen, Dr. William Lehman and Dr. Anthony Cammarato.
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.
Signaling Networks in Heart Failure Progression
With Dr. Brian O’Rourke, we are looking at the impact of mitochondrially-derived reactive oxygen species (ROS) on kinase signaling in the failing heart. ROS impact both gene expression as well as the catalytic activity of many protein kinases and phosphatases. We have recently shown that curbing mitochondrial ROS with a mitochondrially-targeted antioxidant molecule called mitoTempo, both prevents the onset of heart failure and sudden cardiac death (HF/SCD) and rescues HF/SCD. MitoTempo not only blunts the impact of HF on the proteome but preserves the phosphorylation biosignature, by limiting maladaptive MAP kinase signaling and preserving PKA signaling.
Foster DB, Liu T, Kammers K, O’Meally R, Yang N, Papanicolaou KN, Talbot CC, Jr., Cole RN, and O’Rourke B. Integrated omic analysis of a guinea pig model of heart failure and sudden cardiac death. J Proteome Res. 2016. 15(9): p. 3009-3028.
Dey S, DeMazumder D, Sidor A, Foster DB,* and O’Rourke B*. Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure. Circ Res. 2018. 123(3): p. 356-371.