Fig. 11.

D5R mutation induces dilated cardiomyopathy that is related to oxidative stress. D5R deficiency causes an increase in NADPH oxidase activity (I), and prevents the translocation of Nrf2 into the nucleus (II), resulting in a failure of the transcription of a number of antioxidative genes via masculoaponeurotic fibrosarcoma (MAF) and antioxidant response elements (ARE). Antioxidant proteins include NAD(P)H quinone 1 dehydrogenase (NQO1) and heme oxygenase 1 (HO1). Oxidative stress accelerates the signaling of the ERK1/2 and JNK pathway, impairing the balance between apoptosis (BCL2 associated X, apoptosis regulator [BAX]) and anti-apoptosis (B aggressive lymphoma protein 2 (BAL2, PARP14 gene). Phospholamban (PLN) is also stimulated which inhibits cardiac muscle sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA, encoded by ATP2A2), which in turn causes cardiac remodeling and finally, dilated cardiomyopathy. D5R deficiency also allows Kelch-like ECH Associated Protein 1 (Keap1) to target Nrf2 in the cytoplasm for ubiquitination and degradation in the proteasome.