Investigating the role of the adenylyl cyclase inhibitory G protein alpha subunit (Galphai2) in dysfunctional myocardium

Brent Robert DeGeorge, Thomas Jefferson University

Abstract

One of the salient characteristics of the failing heart is an up-regulation of the α-subunit of the adenylyl cyclase (AC) inhibitory heterotrimeric G protein, Gi, both at the protein and transcript level. Recent research has suggested that the up-regulation of Gi is one of several derangements leading to an overall dampened and desensitized β-adrenergic receptor (βAR) signaling system. However, the respective contributions of Gi-G protein-coupled signaling alterations are presently unknown, and a greater understanding of the role of Gi signaling in dysfunctional myocardium is necessary to establish innovative pharmacologic approaches to combat the development of heart failure (HF). Herein, we have specifically targeted and inhibited intracellular Gi signaling in myocytes to define more precisely the role of Gi up-regulation in HF. To this end we have constructed a minigene encoding a peptide inhibitor of Gi signaling. This peptide, which we term GiCT, is comprised of the region of Gαi2 that interacts specifically with the intracellular domains of activated G protein-coupled receptors (GPCRs). We have created a transgenic mouse model with inducible cardiac expression of GiCT, which essentially expresses a functional knockout of Gi signaling in the myocardium. Our central hypothesis was initially that the up-regulation of Gi in dysfunctional myocardium plays a critical role in the pathogenesis of HF and that targeted inhibition of Gi signaling would lead to amelioration of cardiac dysfunction; however this research has demonstrated that the up-regulation of Gi signaling appears to perform a protective function, at least acutely. Inducible, cardiac-specific GiCT transgenic mice (Tg-GiCT), display a baseline phenotype consistent with non-transgenic (nTg) mice. However, when subjected to ischemia/reperfusion (I/R) injury, Tg-GiCT mice demonstrate a significant increase in infarct size compared to nTg. Mechanistically, this post-I/R phenotype includes increased myocardial apoptosis and resultant decreased contractile performance. Overall, our results demonstrate the in vivo utility of GiCT to dissect specific mechanisms attributed to Gi signaling in stressed myocardium. Our results with GiCT indicate that up-regulation of Gαi2 is an adaptive protective response post-ischemia to shield myocytes from apoptosis. ^

Subject Area

Health Sciences, Pharmacology

Recommended Citation

Brent Robert DeGeorge, "Investigating the role of the adenylyl cyclase inhibitory G protein alpha subunit (Galphai2) in dysfunctional myocardium" (January 1, 2008). ETD Collection for Thomas Jefferson University. Paper AAI3416526.
http://jdc.jefferson.edu/dissertations/AAI3416526

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