Professor of Medicine
Director, Cardiovascular Metabolism Program
Penn Cardiovascular Institute, Perelman School of Medicine
Location: Smilow TRC 11-106
Admin: Emily Romick
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. Work over the past few years has focused largely on the role of the vasculature. Examples of ongoing work are:
Blocking fat transport to treat diabetes.
We are studying novel mechanisms that regulate the transport of fatty acids from the vascular lumen to the underlying tissue. In the specific case of skeletal muscle, excess such signaling leads to muscle lipotoxicity and insulin resistance. One novel pathway that we have discovered involves the paracrine secretion by muscle cells of 3-hydroxyisobutyrate, a metabolite of valine, which in turn promotes endothelial transport of excess fatty acids to skeletal muscle. Understanding and targeting this pathway could lead to novel therapies that go at the root of insulin resistance and diabetes.
Understanding systemic metabolism of branched chain amino acids (BCAAs).
The observation above that a metabolite of valine critically influences insulin resistance, combined with the longstanding knowledge that elevations in BCAAs promote insulin resistance in humans, has led us to query how BCAAs are handled, partitioned, and oxidized by the entire organism. To address this question, we are using state-of-the-art LC/MS-based studies on live conscious mice infused at steady-state with heavy isotope tracers. BCAA handling is then interrogated under various physiological and pathological situations, such as pregnancy or heart failure.
Getting at the heart of pregnancy.
Some women who are pregnant or 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, we demonstrated that the heart failure is vascular in nature, in part driven by anti-vascular hormones secreted by the placenta, i.e. PPCM is a vasculo/hormonal disease. And second, we identified in ~10% of women with PPCM, loss-of-function mutations in the gene TTN, encoding for the large sarcomeric protein titin. A major focus of the lab currently is to understand how TTN mutations cause disease, and how they synergize with placenta-derived toxic hormones during pregnancy, with the ultimate goal to identify treatments for this devastating disease
Understanding endothelial metabolism.
When new blood vessels are needed, for example to repair a wound or in a growing tumor, endothelial cells activate, grow rapidly, invade tissues that lack oxygen and nutrients, and form new blood vessels. In this way, endothelial cells act very much like cancer cells. Leveraging the monumental findings that are being made in cancer metabolism, we are seeking to understand how endothelial metabolism affects the unique biological roles of endothelial cells, e.g. supporting wound healing, nutrient transport, or maintaining barrier function. Recent examples include understanding the role of glutamine in ECs, or the role of the pyruvate kinase M2 isoform, to date almost exclusively studied in cancer cells.
Teasing apart critical metabolic pathways.
The mTOR pathway sits at the center of intracellular metabolic regulation, and yet almost nothing is known of how individual input signals to mTOR yield to different outputs, i.e. how mTOR is not simply one master on/off switch. We have identified one such mechanism, in which the protein folliculin promotes mTOR to phosphorylate and suppress one branch of mTOR signaling (the TFE and PGC-1 family of transcription regulators), but has not impact on another branch (canonical signaling to S6K). We are actively studying the underlying molecular mechanism for this specificity, as well as the physiological implications in various contexts, such as adipose tissue and immune cells.
- Ware JS, Li J, Mazaika E, Yasso CM, DeSouza T, Cappola TP, Tsai EJ, Hilfiker-Kleiner D, Kamiya CA, Mazzarotto F, Cook SA, Halder I, Prasad SK, Pisarcik J, Hanley-Yanez K, Alharethi R, Damp J, Hsich E, Elkayam U, Sheppard R, Kealey A, Alexis J, Ramani G, Safirstein J, Boehmer J, Pauly DF, Wittstein IS, Thohan V, Zucker MJ, Liu P, Gorcsan J 3rd, McNamara DM, Seidman CE, Seidman JG, Arany Z. Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies. N Engl J Med. 2016 Jan 21;374(3):233-41.
- C. Jang, SF Oh, S Wada, GC Rowe, L Liu, MC Chan, J Rhee, A Hoshino, B Kim, A Ibrahim, LG Baca, E Kim, CC Ghosh, SM Parikh, A Jiang, Q Chu, DE Forman, SH Lecker, S Krishnaiah, JD Rabinowitz, A Weljie, JA Baur, DL Kasper, Z Arany. A branched chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nature Medicine. 2016. Apr;22(4):421-6 (Featured in NIDDK Recent Advances and Emerging Opportunities 2017)
- Wada S, Neinast M, Jang C, Ibrahim YH, Lee G, Babu A, Li J, Hoshino A, Rowe GC, Rhee J, Martina JA, Puertollano R, Blenis J, Morley M, Baur JA, Seale P, Arany Z. The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate browning of adipose tissue. Genes Dev. 2016 Nov 15;30(22):2551-2564.
- Kim B, Li J, Jang C, Arany Z. Glutamine fuels proliferation but not migration of endothelial cells. EMBO Journal. 2017 Aug 15; 36: 2321-2333. PMID 28659379. (Cover art, and featured in same-issue Editorial)
- Das A, Huang GX, Bonkowski M, Longchamp A, Li C, Schultz MB, Kim LJ, Osborne O, Joshi S, Kang MJ, Lu Y, Hung T, Lee B, Williams EO, Igarashi M, Mitchell JR, Wu LE, Turner N, Arany Z*, Guarente LP*, and Sinclair DA*. Impairment of an endothelial NAD+-H2S signaling network is a reversible cause of vascular aging. Cell. 2018 Mar 22;173(1):74-89.e20. *co-senior authors
- Patten IS, Rana S, Shahul S, Rowe GC, Rhee JS, Jang C, Liu L, Hacker MR, Mitchell J, Mahmood F, Hess P, Bauersachs J, Hilfiker-Kleiner D, Karumanchi SA, Arany Z. Cardiac Angiogenic Imbalance Leads to Peripartum Cardiomyopathy. Nature. 2012 May 9;485(7398):333-8. PMCID 3356917 Featured in Institute of Medicine (IOM) report on Clinical and Translational Science Awards Program