Abstract 030: Cardiac-specific Expression Of Constitutively Active Sumo-2 In Mice Leads To Cardiomyopathy
Sumoylation is a versatile posttranslational modification that regulates a wide spectrum of cellular activities and is involved in a number of human diseases. Cardiomyopathy is the leading cause of heart failure. Whether and how sumoylation is implicated in cardiomyopathy has not been well investigated. To address this issue, we generated a number of independent transgenic mouse lines that express constitutively active SUMO-2 in hearts (SUMO-2-Tg). Four of five SUMO-2-Tg mouse lines exhibited cardiomyopathy with various severities, ranging from acute heart failure leading to early death to hypertrophic cardiomyopathy which developed gradually as mice aged. An increase in apoptosis was observed in the SUMO-2-Tg hearts prior to the occurrence of any other discernible heart phenotypes. Adenovirus-mediated expression of SUMO-2 in cultured cardiomyocytes significantly increased Annexin V staining, indicating that SUMO-2 directly promoted the apoptotic process. We further revealed that SUMO-2 was directly involved in regulation of apoptosis at least partially via targeting calpain 2 (Capn2) and its natural inhibitor calpastatin (CAST). SUMO attachment to CAST mainly promoted its turnover, thus inhibiting CAST activity. On the other hand, SUMO-2 linkage to Capn2 increased its capacity to promote apoptosis, as evidenced by the observation that adenovirus-aided expression of SUMO-fused Capn2 (SUMO-Capn2) in cultured cardiomyocytes significantly promoted Annexin V staining compared with free Capn2. We also observed that SUMO-2/3 conjugation was significantly increased in the human failing hearts compared with the control hearts. Correspondingly, elevated levels of SUMO-2/3-conjugated Capn2 and CAST were detected in the human failing hearts vs. control hearts. Thus, elevated SUMO-2 conjugation led to increased apoptosis and cardiomyopathy at least partially via targeting calpain-calpastatin proteolytic system. The present study uncovers a direct regulation of the apoptotic pathway by the SUMO-2/3 conjugation pathway.
- © 2013 by American Heart Association, Inc.