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    • According to the present observations

    2024-03-28

    According to the present observations, the Ampkα1 isoform promotes AP-1 transcriptional activity and thereby fosters BS-181 sale of AP-1 target genes in cardiomyocytes via activation of Pkcζ. The transcription factor AP-1 plays a decisive role during cardiac remodeling [24], [25], [26], [37]. AP-1 modulates the effects of pressure overload [38] and mediates the up-regulation of its target gene Ncx1 upon beta-adrenergic stimulation [28] contributing to cardiac dysfunction in the failing heart [28], [39]. AP-1 furthermore controls myocardial Il6 expression [30]. Especially chronic elevation of Il6 is linked with heart failure [40]. In accordance with the results observed in this study, AP-1 controls the fetal gene expression profile associated with cardiac remodeling through c-Fos, but is not critical for the hypertrophic response [29]. Thus, AP-1 plays a rather complex role in cardiomyocytes and appears to be of particular importance in the transition from cardiac hypertrophy to failure [24]. Besides its chronic effects during heart failure, AP-1 limits the acute inflammatory response after cardiac ischemia/reperfusion [41] by increasing Il6[40]. Cardiac ischemia increases Ampkα1 activity [42]. Reduced Ampkα1 and Ampkα2 activity after cardiac ischemia reperfusion results in increased cardiac injury [43]. Hypothetically, cardiac AP-1 activation by Ampkα1 may ameliorate ischemia reperfusion injury. Furthermore, Ampkα1 blunts myocardial edema during sepsis by preservation of vascular barrier function [44]. Theoretically this effect could also involve AP-1 regulation by Ampkα1, as AP-1 may be involved in endothelial barrier repair [45]. Ampkα1 mediates AP-1 activation in cardiac cells, at least partly, via activation of Pkcζ. Previous findings demonstrated an up-regulation of Pkcζ in rodent and human hypertrophic and failing hearts [46], [47]. Pkcζ activates AP-1 and fosters natriuretic peptide A (Nppa) expression in ventricular myocytes via TRE/AP-1 [31], [48]. An Ampkα1 isoform-specific interaction with Pkcζ has been described previously in alveolar cells, involving Pkcζ phosphorylation and membrane translocation [4], [11]. Accordingly, both TAC and angiotensin-II infusion, as well as AAV9-mediated expression of constitutively active Ampkα1 resulted in an increased abundance of Pkcζ observed at the intercalated disk. Silencing of Ampkα1 and Pkcζ, but not of Ampkα2, prevented the increase of AP-1 target gene expression after angiotensin-II treatment. Accordingly, Pkcζ inhibition is protective following pressure overload [49]. Furthermore, the pathological cardiac gene expression pattern induced by angiotensin-II is ameliorated in Pkcζ-deficient mice [50]. Taken together, the effects of Ampk may depend on the isoform of the catalytic Ampkα subunit [6], [11], [15]. Ampk activity is increased following pressure overload [14]. Ampkα2 has profound protective effects in the stressed heart [1], [2], [3]. Ampk is important for cardiac mitochondrial function [51], [52]. Especially Ampkα2 was implied as a regulator of mitochondrial function, an effect discussed to counteract cardiac remodeling [53], [54]. Cardiac Ampkα1 seems to have less importance on the regulation of mitochondrial enzymes [33]. Our observations suggest that the two Ampkα isoforms have distinct effects in cardiomyocytes, as constitutively active Ampkα2 overexpression did not mimic the effects of constitutively active Ampkα1 overexpression on the expression pattern of AP-1 target genes. Similarly, pharmacological activation of Ampk is associated with beneficial effects in the failing heart, but the effects of the pharmacological activators may be independent of Ampk [33]. AICAR up-regulated c-Fos expression, but was not able to mimic the effects of Ampkα1 overexpression and down-regulated expression of the AP-1 target genes Il6 and Ncx1. AICAR has, however, been recognized to have numerous Ampk-independent effects [54], [55]. The results in this study suggest that the previously observed shift from Ampkα2 to Ampkα1 in human heart failure may result in significant negative pathophysiological consequences in the failing heart, where AP-1 induces a fetal gene expression profile [13]. According to the present observations, modifying or preventing the isoform shift in the failing heart, rather than Ampk activation, may favorably influence the clinical course of cardiac disease.