Cardiac Reanimation: Targeting Cardiomyocyte Death by BNIP3 and NIX/BNIP3L

Oncogene (2009) 27, S158–S167 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc REVIEW Cardiac reanimation: targeting cardiomyocyte death by BNIP3 and NIX/BNIP3L GW Dorn II1 and LA Kirshenbaum2 1Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St Louis, MO, USA and 2Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada Programmed cardiac myocyte death contributes to are induced in response to cardiac injury or stress, in pathological ventricular remodeling and the progression development of heart failure, and describe the potential of myocardialinfarction or pressure overloadhypertrophy to prevent heart failure by interrupting BNIP3- and to dilated cardiomyopathy. Recent work has identified NIX/BNIP3L-mediated programmed cardiomyocyte importance of stress-mediated transcriptionalinduction of death. BNIP3 (BCL2 and 19-kDa interacting protein-3) and NIX/BNIP3L in cardiac remodeling. Here, the regulatory mechanisms for these two factors in the heart and their effects on programmed cardiomyocyte death are reviewed, Primary or secondary cardiomyocyte loss and the path with a focus on information derived from studies using to heart failure mouse models of cardiac BNIP3 and NIX/BNIP3L overexpression and gene ablation. Heart failure is a clinical syndrome defined as any Oncogene (2009) 27, S158–S167;doi:10.1038/onc.2009.53 condition where the rate of blood delivery to systemic tissues is insufficient to meet their metabolic needs. This Keywords: apoptosis;autophagy;heart failure;cardiac definition includes situations where myocardial function hypertrophy;myocardial infarction is normal and cardiac output (the volume of blood pumped per unit of time, B5 l/min in humans) is within accepted parameters or increased, such as in profound anemia and arteriovenous communications (shunts). However, the overwhelming majority of clinical heart Introduction failure cases are the consequence of primary myocardial dysfunction, with depressed cardiac output. In North The goal of revitalizing dead tissue is almost as old as America and Europe, heart failure is largely attributable our ability to understand the differences between life to ischemic or hypertensive cardiomyopathy, with and death. The biblical Lazarus miracle used the power genetic disorders, sleep apnea, viral, toxic and peripar- of God to restore life. In Mary Shelley’s Frankenstein, tum myocardial disease accounting for most other cases electricity provided the spark of life to the monster. (Hunt et al., 2005). Herbert West, a medical student in the HP Lovecraft’s Primary myocardial dysfunction leading to heart short story that was popularized in a series of the 1980s failure can be temporary, as with alcoholic cardiomyo- ‘Re-Animator’ horror movies, used chemical solutions to pathy and post-ischemic myocardial ‘stunning’ (Bolli revitalize small animals and, eventually, the Dean of the and Marban, 1999). More commonly, however, heart medical school (with unfortunate consequences). Now, failure is irreversible because it results from the physical modern tools of genetic manipulation and an explosion loss of functioning cardiac myocytes, so-called ‘cardio- in our understanding of the molecular processes that myocyte dropout’ (Diwan and Dorn, 2007). In coronary lead to cell death provide an opportunity not to bring atherosclerosis and ischemic heart disease, cardiomyo- dead tissue to life, but to interrupt intrinsic pathways cyte dropout tends to be focal, whereas it is more diffuse leading to predetermined cell death. The promise of this in nonischemic failure (Berry et al., 1993;Olivetti et al., approach is especially great in the heart, where tissue 1997). Importantly, the loss of functional contractile regeneration after injury does not occur to a meaningful units of the heart and their replacement by fibrous scar extent. Here, we review recent developments delineating or diffuse interstitial fibrosis produces secondary struc- the functions of BNIP3 (BCL2 and 19-kDa interacting tural changes in the ventricles that increase the work protein-3) and NIX/BNIP3L, two cell suicide genes that required for ventricular contraction. Surviving myocytes slip past one another and elongate as the extracellular Correspondence: Professor GW Dorn II, Department of Medicine, matrix remodels (Olivetti et al., 1990;Francis, Center for Pharmacogenomics, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8086, St Louis, MO 63110, 1998). Cardiomyocyte dropout and slippage produce USA. ‘ventricular remodeling’, resulting in an enlarged, thin- E-mail: [email protected] walled ventricle. These two factors, wall thinning and Targeting cardiomyocyte death GW Dorn II and LA Kirshenbaum S159 chamber dilation, strikingly increase the force that Ischemia Hypertrophy opposes ventricular contraction and blood ejection into HIF1α PKC the aorta. A mathematical description of this physical gene transcription Sp1 relationship was developed by the eighteenth century inactive French physicist, Pierre Laplace, and reveals that wall cytosolic stress (in the heart, afterload) is directly proportional to BNIP3 the radius of the chamber (r) and its intracavitary post-translational pressure (p), and is inversely proportional to the processing chamber wall thickness (h);stress ¼ pr/2h. Thus, any active active primary injury to the heart that causes cardiomyocyte mitochondrial mitochondrial NIX/BNIP3L dropout and ventricular remodeling produces a second- BNIP3 BCLXL ary stress on the heart in the form of increased afterload that is chronic and unremitting (Grossman et al., 1975). Studies performed over the past decade have shown that Proteasome Proteasome this hemodynamic stress is a powerful stimulus for programmed cardiomyocyte death, initiating a vicious cycle of unfavorable geometrical remodeling that stimulates yet more cell death (Foo et al., 2005;Dorn Post MI LV cyt c Hypertrophic II, 2009). The ultimate consequence, notwithstanding remodeling, Caspases LV remodeling the nature of the inciting stimulus, is a downward Diminished EF Apoptosis Diminished EF functional spiral progressing to dilated cardiomyopathy Figure 1 Transcriptional regulation of BNIP3 and NIX/BNIP3L. and end-stage heart failure. Separate pathways upregulate BNIP3 and NIX/BNIP3L in myocardial ischemia and hypertrophy, respectively, but they share a common apoptosis effector pathway. HIF-1a, hypoxia-inducible factor 1a;PKC, protein kinase C;Cyt c, cytochrome c. Cardiomyocyte apoptosis and BCL2 proteins in myocardialdisease death receptor pathways or the intrinsic, mitochondrial The cycle of cardiomyocyte dropout and ventricular pathway. As the focus of this review is on two mediators remodeling is chronic and persistent after a primary of mitochondrial pathway apoptosis, BNIP3 and NIX/ cardiac insult. This provides a therapeutic window of BNIP3L, the interested reader is referred to other recent months to years to implement targeted interventions reviews of extrinsic apoptosis in the heart and elsewhere that can interrupt the cycle and prevent progression to (Ashkenazi and Dixit, 1999;MacEwan, 2002;Danial end-stage heart disease. Furthermore, current under- and Korsmeyer, 2004). standing suggests that chronic cardiomyocyte dropout is The key initiators, regulators and effectors of intrinsic overwhelmingly an active process mediated by distinct, pathway apoptosis are the BCL2 family of mitochon- but functionally redundant, cell signaling pathways that drial-targeted pro- and antiapoptotic proteins. Cardiac lead to different forms of programmed cardiomyocyte myocytes express a number of pro- and antiapoptotic death (Figure 1). This rather complicated biology BCL2 family proteins that are transcriptionally regu- identified multiple potential therapeutic targets for lated in heart disease (Latif et al., 2000;Di Napoli et al., preventing ventricular remodeling through inhibition 2003). Proapoptotic BCL2 proteins are classified ac- of factors that cause programmed cardiomyocyte death. cording to structural features that reflect their different Apoptosis has been studied extensively in this regard. functions (Youle and Strasser, 2008). The ‘multidomain’ Myocardium is intrinsically resistant to apoptosis, proteins, BAX and BAK, are the essential pore-forming thought to be due at least in part to high levels of proteins that lead to mitochondrial outer membrane endogenous caspase inhibitors, such as X-linked in- permeabilization, cytochrome c release and induction of hibitor of apoptosis protein (XIAP) and apoptosis the intrinsic apoptosis signaling cascade. The activity of repressor with caspase recruitment domain (ARC) these pore-forming proteins is enhanced by proapopto- (Nam et al., 2004;Siu et al., 2005;Foo et al., 2007). tic ‘BH3 domain-only’ proteins, like BNIP3 and NIX/ Thus, the rate of apoptosis in normal human heart is B1 BNIP3L, and opposed by antiapoptotic factors like per 10 000 cardiomyocytes, but apoptosis increases BCL2 and BCLXL that bind to and inhibit the BH3- several hundred-fold in ischemic and dilated cardiomyo- only proteins. In the heart and elsewhere, the principal pathy and reactive cardiac hypertrophy (Narula et al., function of BH3-only proteins is to sense stress and 1996;Teiger et al., 1996;Olivetti et al., 1997). Because initiate mitochondrial translocation of BAX or activa- adult cardiac myocytes are incapable of meaningful tion of mitochondrial

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