Intracardiac injection of AdGRK5-NT reduces left ventricular hypertrophy by inhibiting NF-kappaB-dependent hypertrophic gene expression.
Several studies underline the role of the transcription factor NF-κB in the development of left cardiac hypertrophy (LVH). We have demonstrated recently that the RGS homology domain within the amino terminus of GRK5 (GRK5-NT) is able to inhibit NF-κB transcription activity and its associated phenotypes. The aim of this study was to evaluate the ability of GRK5-NT to regulate LVH through the inhibition of NF-κB both in vitro and in vivo. In cardiomyoblasts, GRK5-NT inhibits phenylephrine-induced transcription of both NF-κB and atrial natriuretic factor promoters, assessed by luciferase assay, thus confirming a role for this protein in the regulation of cardiomyocyte hypertrophy. In vivo, we explored 2 rat models of LVH, the spontaneously hypertensive rat and the normotensive Wistar Kyoto rat exposed to chronic administration of phenylephrine. Intracardiac injection of an adenovirus encoding for GRK5-NT reduces cardiac mass in spontaneously hypertensive rats and prevents the development of phenylephrine-induced LVH in Wistar Kyoto rats. This associates with inhibition of NF-κB signaling (assessed by NF-κB levels), transcriptional activity and phenotypes (fibrosis and apoptosis). Such phenomenon is independent from hemodynamic changes, because adenovirus encoding for GRK5-NT did not reduce blood pressure levels in spontaneously hypertensive rats or in Wistar Kyoto rats. In conclusion, our study supports the regulation of LVH based on the GRK5-NT inhibition of the NF-κB transduction signaling.
Sorriento
Daniela
D
Department of Clinical Medicine, Cardiovascular and Immunologic Sciences, Federico II University, Naples, Italy.
Santulli
Gaetano
G
Fusco
Anna
A
Anastasio
Antonio
A
Trimarco
Bruno
B
Iaccarino
Guido
G
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure; D015153:Blotting, Western; D002460:Cell Line; D004452:Echocardiography; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020672:I-kappa B Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D000072000:NF-KappaB Inhibitor alpha