Dickkopf-3: a stubborn protector of cardiac hypertrophy.

In response to haemodynamic overload under pathological conditions such as hypertension, valvular heart disease, and myocardial infarction, the heart undergoes hypertrophic growth by increasing cell size and protein synthesis as well as changing the transcriptional programme in cardiac myocytes. Although cardiac hypertrophy is beneficial in the way that it reduces ventricular wall tension and maintains pump function, it promotes cardiac structural remodelling and dysfunction, and eventually leads to development of congestive heart failure, arrhythmia, and sudden death. At present, several drugs such as inhibitors of the renin–angiotensin–aldosterone system, b-adrenergic receptor blockers, and calcium channel blockers are clinically available for the management of hypertension, and these drugs have shown significant efficacy in preventing load-induced cardiac hypertrophy and remodelling. However, these pharmacological agents are currently of limited effectiveness, and further discovery and development of novel classes of cardioprotective drugs are in urgent need. For that purpose, it is important to elucidate the molecular mechanisms underlying the development of cardiac hypertrophy. In the article by Zhang et al., integrating genetic approaches in mice have shed light on Dickkopf-3 (DKK3) as a cardioprotective regulator of cardiac hypertrophy. DKK3 is a secreted glycoprotein of the Dickkopf family that typically antagonizes the Wnt/b-catenin signalling by interfering with Wnt co-receptors, low-density lipoprotein receptor-related protein and kremen. ‘Dickkopf’ is a German word for ‘big head’ or ‘stubborn’, and the protein family owes its name to the finding that DKK1 is sufficient and necessary to induce head formation in Xenopus embryo. Zhang et al. first demonstrated that cardiac expression of DKK3 was downregulated in patients with end-stage heart failure and in mice with pressure-overloaded cardiac hypertrophy. In neonatal rat cardiac myocyte cultures, angiotensin II-induced hypertrophic responses were enhanced by siRNA-mediated knockdown of DKK3, and conversely were attenuated by overexpression of DKK3. Consistently, cardiac hypertrophy following aortic banding in mice was enhanced by genetic disruption of DKK3, and was attenuated by transgenic overexpression of DKK3. These lossand gain-of-function analyses, both in vitro and in vivo, indicated the regulatory role of DKK3 in protecting the heart from the development of pathological cardiac hypertrophy. The next obvious question is how DKK3 affects the signalling effectors underlying pathological hypertrophy and remodelling of the heart. Zhang et al. demonstrated that DKK3 inhibited the activation of apoptosis signalregulating kinase 1 (ASK1), and thereby suppressed the activation of its downstream effectors c-Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinases (MAPKs) in hearts subjected to hypertrophic stimulation (Figure 1). Importantly, DKK3 overexpression attenuated the activation of ASK1 in pressure-overloaded hearts of mice, and restoration of ASK1 activity by transgenic overexpression abolished the protective effects of DKK3 overexpression against pressure overload-induced cardiac remodelling. Conversely, disruption of DKK3 enhanced the ASK1 activation in pressure-overloaded hearts, and inactivation of ASK1 by transgenic overexpression of a dominant negative mutant prevented exaggeration of pressure overload-induced cardiac remodelling in DKK3-deficient mice. ASK1 is a key component of a high molecular mass complex, termed the ASK1 signalosome, and is activated in response to a variety of cellular stresses, such as reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, calcium overload, and inflammatory signals mediated by tumour necrosis factor-a (TNF-a) and lipopolysaccharide. While the ASK1 activity is suppressed by the reduced form of thioredoxin (Trx) (a redox-sensitive protein) within the ASK1 signalosome, oxidation of Trx in response to ROS induced autophosphorylation and oligomerization of ASK1, leading to its activation. Upon ROS-stimulated activation, adaptor proteins, such as TNF-a receptor-associated factor 2 (TRAF2) and TRAF6, and USP9X deubiquitination enzyme are recruited to the signalosome to maintain full activation of ASK1 (Figure 1). Although the precise mechanism by which DKK3 inhibits ASK1 activation remains unclear, Zhang et al. demonstrated, by co-immunoprecipitation experiments, that exogenously expressed DKK3 and ASK1 formed a complex in HEK293 T cells, and furthermore showed direct interaction between endogenous DKK3 and ASK1 in neonatal rat cardiac myocytes. These results suggest that DKK3 may interfere with ASK1 activation via the physical interaction with ASK1 within the signalosome (Figure 1), but