Research in the Arany Lab
The Arany lab is interested in all things cardiovascular metabolism. The ideal project leverages multi-disciplinary tools and approaches, and spans from molecular mechanistic work, to murine models of disease, to human studies. We take multidisciplinary approaches, ranging from molecular biology and high-throughput metabolomics (e.g. C13 flux analyses) and genomics to cell biology, mouse physiology, and human genetics. Our goal is to understand events that underlie physiological and pathological metabolic adaptations in heart, skeletal muscle, and the vasculature.
Current Topics of Interest
COVID-19 has devastated the world. Cardiovascular disease, including cardiomyopathy, are a prominent feature.
Preexisting cardiovascular and metabolic diseases are strong risk factors for adverse clinical course, and cardiac damage is one of the strongest predictors for rates of fatality. We have ongoing projects evaluating the effects on SARS-CoV2 on vasculature and cardiomyocytes, testing the hypothesis that direct cardiovascular damage to these cells by the virus underlies adverse clinical outcomes.
Understanding cardiac metabolism is at the core of the lab’s interests.
We have published extensively on this topic for 15 years, including seminal work on the role of PGC-1alpha in the heart. Most recently, we demonstrated a surprise role for adenine nucleotide transporter (ANT) in controlling mitophagy, with important implications for cardiac disease (Nature 2019). Current projects vary widely, including deep LC-MS metabolomic evaluation of arterio-venous changes in plasma nutrients, using blood from artery and coronary sinus of patients in the electrophysiology lab (see figure); generation and evaluation of genetic mouse models of ANT; leveraging human post-transplant hearts to probe metabolic mechanisms in cardiomyocytes; and studies focused on right heart failure, an often ignored but clinically significant component of heart failure.
1. How is vascular metabolism regulated by the underlying parenchyma (e.g. skeletal muscle or heart)? We published seminal work identifying PGC-1alpha in skeletal muscle as a key driver of cross-talk with endothelial cells, driving angiogenesis (Nature 2008) and transport of nutrients (Nature Medicine 2016). Projects are ongoing to further understand the molecular mechanisms of endothelial-parenchymal crosstalk, with a particular focus on fatty acid transport (see Cell Metabolism 2020) and its consequences on insulin resistance and diabetes.
2. How does metabolism within the endothelial cell affect vascular function? Endothelial cells are metabolically fascinating: largely quiescent, but metabolically very similar to tumor cells, including having a markedly strong Warburg effect at baseline. We have recently reported on surprising roles of glycolytic enzymes (JCI 2018), glutamine enzymes (EMBO 2017), and NAD-consuming SIRT1 (Cell 2018) in endothelium. Numerous active projects in the lab include understanding the role of NAD biology and lipid handling in the endothelium, and the consequences on diabetes, heart failure, and atherosclerosis.
Branched chain amino acids (BCAAs: leucine, valine, and isoleucine) have taken center stage recently as potential contributors to insulin resistance, heart failure, and other pathologies.
We reported recently that 3-hydroxyisobutyrate, a metabolite of valine, acts as a paracrine signal to promote lipotoxicity and insulin resistance in muscle (Nature Medicine 2016). This led us to a comprehensive study of how BCAAs are handled, partitioned, and oxidized by the entire organism, using state-of-the-art LC/MS-based studies on live conscious mice infused at steady-state with heavy isotope tracers (Cell Metabolism 2019). Active projects include understanding molecular mechanisms of regulation of BCAA catabolism, and testing the role of BCAA catabolism in insulin resistance, heart failure, and pancreatic cancer.
Getting at the heart of pregnancy and peripartum cardiomyopathy (PPCM).
~1:1000 women who are recently pregnant mysteriously develop profound heart failure, known as peripartum cardiomyopathy (PPCM), often leaving them incapacitated at a critical moment in their life and that of their child. We have made two seminal advances to understanding this disease: first, that PPCM is in part driven by anti-vascular hormones secreted by the placenta, i.e. PPCM is a vasculo/hormonal disease (Nature 2012). And second, that ~10% of women with PPCM bear loss-of-function mutations in the gene TTN, encoding for the large sarcomeric protein titin (New Engl J of Med 2016). A major focus of the lab currently is to probe more deeply into the genetics of PPCM, using international cohorts; to understand racial disparities PPCM (e.g. JAMA Cardiology 2019); and to understand how TTN mutations cause disease (e.g., Circulation 2019), with the ultimate goal to identify treatments for this devastating disease.