Molecular Medicine p90RSK Targets the ERK5-CHIP Ubiquitin E3 Ligase Activity in Diabetic Hearts and Promotes Cardiac Apoptosis and Dysfunction

Rationale: Cardiomyocyte apoptosis is one of the key events in the development and progression of heart failure, and a crucial role for ICER (inducible cAMP early repressor) in this process has been previously reported. ERK5 is known to inhibit cardiac apoptosis after myocardial infarction (MI), especially in hyperglycemic states, via association with CHIP ubiquitin (Ub) ligase and subsequent upregulation of CHIP ligase activity, which induces ICER ubiquitination and subsequent protein degradation. The regulatory mechanism governing ERK5/CHIP interaction is unknown. Objective: We previously demonstrated increased p90RSK activation in the diabetic heart. As a logical extension of this work, we now investigate whether p90RSK activation inhibits ERK5-mediated CHIP activation, and subsequently increases ICER levels and apoptosis. D iabetes mellitus (DM) is an independent risk factor for both mortality and morbidity after myocardial infarction (MI). 1,2 Previously, we have reported that activation of ERK5, an atypical mitogen activated protein kinase with transcriptional activity, 3– 6 inhibits apoptosis and left ventric-ular (LV) dysfunction in DM mice after MI. Sustained elevation of inducible cAMP early repressor (ICER), a proapoptotic transcriptional repressor, 7,8 favors apoptosis through inhibition of the cAMP response element binding protein (CREB)-mediated transcription and downregulation of Bcl-2. 9,10 The protein level of ICER is regulated by CREB-dependent ICER gene transcription as well as proteasome-dependent ICER protein ubiquitination and degradation. 11 We reported that ICER levels were significantly increased in diabetic mice after MI (DMϩMI), and this increase in ICER levels was blunted in transgenic mice expressing a cardiac-specific constitutively active form of MEK5␣ (CA-MEK5␣-Tg). 12 This finding provides a mech-anistic framework for understanding the cardioprotective action of ERK5 in DMϩMI mice via downregulation of ICER levels and inhibition of apoptosis. In a subsequent study we demonstrated that ubiquitination was a critical regulatory mechanism linking ERK5 activation and ICER reduction in DM mice. ERK5 positively regulated chaperone-dependent E3 ubiquitin (Ub) ligase CHIP (car-boxyl terminus of Hsp70-interacting protein)-mediated ICER ubiquitination and subsequent protein degradation. This downregulation of ICER levels leads to maintaining Bcl-2 at high levels, and protects cells from apoptosis. Our studies showed that cardiac CHIP Ub ligase activity was significantly decreased after DMϩMI and this decrease was rectified in CA-MEK5␣-Tg mice. 13 However, the regulatory mechanism underlying this reduction of CHIP Ub ligase activity in DMϩMI mice and how ERK5 activation reversed this phenomenon remains unclear. In this study, we show that the ERK5-CHIP module is one of the major targets of p90RSK …