β-Adrenergic Receptor Signaling Regulates rAAV Transduction through Calcineurin in Heart Muscle Cells

Abstract

Recombinant adeno-associated virus (rAAV)-based gene therapy represents a promising approach for the treatment of heart muscle diseases, but the molecular mechanisms that direct rAAV transduction remain unclear. Here we demonstrate that β-adrenergic receptor stimulation with isoproterenol (ISO) markedly increased cardiomyocyte transduction of rAAV in vitro and in vivo. Conversely, chronic β-adrenergic receptor downregulation significantly suppressed rAAV transduction. Pretreatment with calcium signaling cascade inhibitors including calcineurin inhibitory peptide (CNIP) strongly suppressed the positive effects of ISO on rAAV transduction. Additionally we document that ISO treatment led to a significant increase in double-stranded (ds) DNA synthesis of the rAAV genome and an increase in promoter activity. Moreover, stimulation with ISO did not affect rAAV transduction in calcineurin nullizygous mice. Collectively, we conclude that a calcium-dependent pathway regulates rAAV vector transduction at a number of stages that may include vector mobilization, conversion, and transcription activity. Modulating this pathway through β-adrenergic signaling enhances rAAV-mediated gene delivery to cardiomyocytes, and may be valuable when considering therapeutic approaches for heart muscle diseases.

The Influence of Environmental and Genetic Factors on Various Disorders and Diseases

“…Liposomes have been touted as tumor-specific and effective carriers of cytotoxic drugs. However, they are not devoid of significant problems including premature destruction to cause toxicity to healthy tissues or in the other extreme, undesirably long stability to prevent effective delivery to the tumor cells [44]. Plasma B-type natriuretic peptide (BNP) values have been evaluated as predictors of outcome and are helpful in determination of therapeutic options in patients with both acute and chronic heart failure [45].…”