Popdc1/Bves Functions in the Preservation of Cardiomyocyte Viability While Affecting Rac1 Activity and Bnip3 Expression

Abstract

The Popeye domain containing1, also called Bves (Popdc1/Bves), is a transmembrane protein that functions in muscle regeneration, heart rate regulation, hypoxia tolerance, and ischemia preconditioning. The expression of Popdc1/Bves is elevated in cardiomyocytes maintained in serum free defined medium. We hypothesized that Popdc1/Bves is important for cardiomyocyte survival under the stress of serum deprivation and investigated the mechanisms involved. A deficit in Popdc1/Bves, achieved by siRNA-mediated gene silencing, results in cardiomyocyte injury and death, upregulation of the pro-apoptotic protein Bcl-2/adenovirus E1B 19-kDa interacting protein3 (Bnip3), as well as reduction in Rac1-GTPase activity and in Akt phosphorylation. Combined Popdc1/Bves and Bnip3 silencing attenuated cell injury and prevented Bnip3 upregulation induced by the silencing of Popdc1/Bves alone. Chromatin immunoprecipitation indicated an increased binding of the transcription factor FoxO3 to the Bnip3 promoter although augmentation of FoxO3 in the nuclei was not detected. By contrast, the transcription factor NFκB was excluded from the nuclei of Popdc1/Bves deficient cardiomyocytes and exhibited decreased binding to the Bnip3 promoter. The data indicates that Popdc1/Bves plays a role in the preservation of cardiomyocyte viability under serum deficiency through the alteration of Rac1 activity and the regulation of Bnip3 expression by FoxO3 and NFκB transcription factors pointing to Popdc1/Bves as a potential target to enhance heart protection. J. Cell. Biochem. 118: 1505-1517, 2017. © 2016 Wiley Periodicals, Inc.

The Popeye Domain Containing Genes and Their Function as cAMP Effector Proteins in Striated Muscle

“…Isolated cardiac myocytes from Popdc1 null mutants displayed altered Ca 2+ -transients and increased vulnerability to oxidative stress. Apparently Popdc1 is involved in myocyte survival through the suppression of the pro-apoptotic Bcl2 interacting protein 3 ( Bnip3 ) gene [ 62 ]. While skeletal muscle is not as well studied than cardiac muscle in POPDC null mutants, it has been shown that muscle regeneration is impaired in Popdc1 null mutants, however, the underlying molecular mechanism has yet to be elucidated [ 63 ].…”

New kids on the block: The Popeye domain containing (POPDC) protein family acting as a novel class of cAMP effector proteins in striated muscle

“…Isolated cardiac myocytes from Popdc1 null mutants displayed impaired Ca + 2 -transients, increased vulnerability to oxidative stress and absence of pharmacologic preconditioning. Further studies using myocytes treated with Popdc1 siRNA revealed that Popdc1 is required for cardiac myocyte survival [62] . Loss of Popdc1 causes an increase in the expression of the proapoptotic BCL2 interacting protein 3 ( Bnip3 ), which may explain the increased vulnerability when null mutant hearts are subjected to ischemia/reperfusion injury.…”

The Role of the Popeye Domain Containing Gene Family in Organ Homeostasis

“…Suppression of POPDC1 in myocytes cultured under serum-starved conditions was recently shown to result in cardiomyocyte cell death and the upregulation of Bnip3 [53]. Furthermore, POPDC1 was shown to regulate Bnip3 expression [53]. Interestingly, this is the first dataset linking suppression of POPDC1 to increased cell death and to mitochondrial-mediated mechanisms of regulating cell viability (Figure 3).…”

“…Suppression of POPDC1 in myocytes cultured under serum-starved conditions was recently shown to result in cardiomyocyte cell death and the upregulation of Bnip3 [53]. Furthermore, POPDC1 was shown to regulate Bnip3 expression [53].…”