Mechanisms and novel therapeutic targets in heart failure
Research in the Rosenzweig laboratory is primarily focused on heart failure because it represents both a growing unmet clinical need and an opportunity to study fundamental biological processes including programmed cell death, metabolism, and regeneration with important clinical implications. The laboratory uses a combination of unbiased discovery platforms and hypothesis-driven studies to identify and validate novel therapeutic targets in this context while delineating the underlying biological mechanisms. In addition to studying what goes wrong in heart disease, a growing area of research has been identification of pathways that keep the heart healthy, using the exercised heart as a model.
Earlier studies identified intracellular signaling pathways regulating programmed cell death in cardiomyocytes. This work included the first demonstration that PI3-kinase and Akt1 play an important role in cardiomyocytes, preserving survival and function both in vitro and in vivo. This is particularly relevant to diabetes since these are proximal and important components in the insulin signaling cascade. Subsequent went on to demonstrate that Akt1 controls cardiomyocyte size in vivo through a cell-autonomous mechanism and to define the transcriptional profile of chronic Akt1 activation. Further studies demonstrated that chronic activation of proximal PI3-kinase signaling (as seen in heart failure patients and in hearts of some patients with Type II diabetes) can have adverse consequences through both feedback inhibition of upstream signaling and novel downstream effectors. These studies have identified novel targets amenable to pharmacological intervention in heart failure and arrhythmia, such as SGK1.
The Rosenzweig laboratory is increasingly focused on the intersection of pro-survival signaling mechanisms with those controlling cardiac metabolism. This topic formed the basis for a recently completed Leducq Foundation Transatlantic Network of Excellence, which Dr. Rosenzweig served as the American Coordinator. Related to these studies has been ongoing investigation of the mechanisms that keep the heart healthy, using the exercised heart as a model. Interestingly, these studies suggest that growth of the heart in response to exercise (swimming or running) is fundamentally different from that in response to pathological stimuli such as pressure overload. Moreover, exercise induces a proliferative and potentially regenerative response in the heart. Comprehensive genome-wide analyses and validation of transcription factors and micro-RNAs differentially expressed in these models has identified candidate pathways we hypothesize mediate the cardioprotective and regenerative effects of exercise. Multiple ongoing projects seek to exploit these pathways to enhance recovery and cardiac function after ischemic injury.
1. Boström P, Mann N, Wu J, Quintero PA, Plovie ER, Panáková D, Gupta RK, Xiao C, MacRae CA, Rosenzweig A, Spiegelman BM.C/EBPβ controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell. 2010 Dec 23;143(7):1072-83. PMCID:PMC3035164
2. Ashida N, Senbanerjee S, Kodama S, Foo SY, Coggins M, Spencer JA, Zamiri P, Shen D, Li L, Sciuto T, Dvorak A, Gerszten RE, Lin CP, Karin M, Rosenzweig A. IKKβ regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways. Nat Commun. 2011;2:318. PMCID: PMC3113230
3. Aoyagi T, Kusakari Y, Xiao CY, Inouye BT, Takahashi M, Scherrer-Crosbie M, Rosenzweig A, Hara K, Matsui T.Cardiac mTOR protects the heart against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2012 Jul;303(1):H75-85. PMCID:PMC3404649
4. Das S, Aiba T, Rosenberg M, Hessler K, Xiao C, Quintero PA, Ottaviano FG, Knight AC, Graham EL, Boström P, Morissette MR, del Monte F, Begley MJ, Cantley LC, Ellinor PT, Tomaselli GF, Rosenzweig A. Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling. Circulation. 2012 Oct 30;126(18):2208-19.PMCID:PMC3484211
5. Zarrinpashneh E, Poggioli T, Sarathchandra P, Lexow J, Monassier L, Terracciano C, Lang F, Damilano F, Zhou JQ, Rosenzweig A, Rosenthal N, Santini MP. Ablation of SGK1 impairs endothelial cell migration and tube formation leading to decreased neo-angiogenesis following myocardial infarction. PLoS One. 2013 Nov 12;8(11):e80268. PMCID:PMC3827188
6. Dai J, Matsui T, Abel ED, Dedhar S, Gerszten RE, Seidman CE, Seidman JG, Rosenzweig A. Deep sequence analysis of gene expression identifies osteopontin as a downstream effector of integrin-linked kinase (ILK) in cardiac-specific ILK knockout mice. Circ Heart Fail. 2014 Jan;7(1):184-93.PMCID:PMC3950354 [Available on 2015/1/1]
7. North BJ, Rosenberg MA, Jeganathan KB, Hafner AV, Michan S, Dai J, Baker DJ, Cen Y, Wu LE, Sauve AA, van Deursen JM, Rosenzweig A, Sinclair DA. SIRT2 induces the checkpoint kinase BubR1 to increase lifespan.EMBO J. 2014 May 12. pii: e201386907. [Epub ahead of print]