β-Adrenergic stimulation induces cardiac ankyrin repeat protein expression: involvement of protein kinase A and calmodulin-dependent kinase

Abstract

Our study provides the first evidence that overexpression of CARP, which is thought to act as a transcriptional co-repressor, may deteriorate contractile function of the heart tissue. Furthermore, beta-adrenoceptor stimulation and activation of PKA and CaMK have been identified as mechanisms that induce expression of CARP in cardiomyocytes.

The enigmatic role of the ankyrin repeat domain 1 gene in heart development and disease

“…At the immunoelectron-microscopy level, ANKRD1/ CARP epitopes were detected in the central I-band, as well as, within the nucleolus of mouse fetal (Miller et al, 2003) and postnatal (Bang et al, 2001) cardiomyocytes. Consistent with these findings, FLAG- (Jeyaseelan et al, 1997) or GFP-tagged (Miller et al, 2003;Zolk et al, 2003) ANKRD1/CARP was localized in both the nucleus and cytoplasm of transfected neonatal rat cardiomyocytes. ANKRD1/CARP is enriched in the insoluble myofibrillar bound fraction (Torrado et al, 2005a;Hayashi et al, 2008), consistent with its strong binding to titin and myopalladin.…”

“…At first glance, these results point to ankrd1 up-regulation as the end-stage DCM-specific feature which might be responsible for dysregulation of gene expression in failing DCM-myocardium (Zolk et al, 2002;Baudet, 2003;Zolk et al, 2003). However, ankrd1 expression has been demonstrated to be up-regulated in the LV at various different pathophysiological states, namely, in animals models of cardiac hypertrophy (Kuo et al, 1999;Aihara et al, 2000;Johnatty et al, 2000), non-lethal cardiac ischemia (Depre et al, 2001), genetically induced (Gotthardt et al, 2003) or cardiotoxic CM (Torrado et al, 2004;Torrado et al, 2006), and in the heart of animals with streptozotocin-induced diabetes (Lehti et al, 2007) as well as, in patients with ischemic CM (Zolk et al, 2002) or ventricular septal defects (Zhang et al, 2006).…”

“…Later, it has been demonstrated that DCM-like phenotypes resulted from very different initial insults are also associated with a strong ankrd1 up-regulation in the LV myocardium (Table 2 and references wherein). Further, ankrd1 mRNA and protein levels were significantly increased in LV myocardium samples obtained from patients with end-stage HF due to idiopathic non-ischemic DCM (Zolk et al, 2003;Nagueh et al, 2004;Torrado et al, 2005b). Cardiac-tissue fractionation experiments followed by Western blot identification suggested that ANKRD1/CARP is mainly localized in nuclei and weakly expressed in the cytoplasm of human failing and non-failing myocardium (Zolk et al, 2002).…”

Intron retention generates ANKRD1 splice variants that are co-regulated with the main transcript in normal and failing myocardium

“…In mice, a total ankrd1 knockout resulted in a complete lack of phenotype (Barash et al, 2007), suggesting that ANKRD1 is not crucial for regulation of cardiac gene expression in vivo, as it has been proposed in the past (Zolk et al, 2002(Zolk et al, , 2003. However, ankrd1 augmented expression can represent an adaptive response of the myocardium to stress both during development and various heart insults .…”

“…Although a high stress-induced level of the ankrd1 mRNA results from a rapid burst of gene transcription (Kanai et al, 2001), it is increasingly more recognized that posttranscriptional regulation can also be an important mechanism in terms of controlling ankrd1 transcript and protein abundance (Zolk et al, 2003;Samaras et al, 2007;Witt et al, 2008).…”