Author

Maya Ramdas

Advisor

Pulakat, Lakshmi

Committee Member

Gordon, Donna

Committee Member

Wise, Dwayne

Committee Member

Boyle, John

Committee Member

Gavini, Nara

Date of Degree

1-1-2009

Document Type

Dissertation - Open Access

Major

Biology

Degree Name

Doctor of Philosophy

College

College of Arts and Sciences

Department

Department of Biological Sciences

Abstract

Molecular analysis of the cross talk between Angiotensin II (Ang II) and insulin signaling systems reveal that they are multifaceted and occur at cellular level and intracellular level. Experiments were carried out to evaluate the crosstalk between the Ang II receptors-AT1 and AT2 and the Insulin Receptor (IR) to understand the changes in the signaling pathway that could lead to the transition from hypertension to insulin resistance. Transient expression of rat AT2 in CHO cells induced co-immunoprecipitation of the AT2R with IRâ and inhibition of IRâ tyrosine phosphorylation. An AT2-peptide carrying the amino acids 226-363 (that spans 3rd intracellular loop (ICL) and C-terminal cytoplasmic domain) was sufficient for AT2- IRâ interaction in a yeast two-hybrid assay. An orthovanadate-insensitive AT2- IRâ association was also observed in human breast cancer cell line MCF-7. Interestingly, while AT2- IRâ complex formation was insensitive to pertussis toxin (PTX), AT2-mediated inhibition of IRâ phosphorylation was partially sensitive to PTX treatment in MCF-7. To address the mechanism behind the transition of an early hypertensive heart to an insulin resistant status, we investigated the changes that occur at post translational level in the IR and its downstream signaling molecules that modulate insulin signaling. Early hypertension was induced in 10-week old SD rats by 2% NaCl diet in combination with Ang II infusion. Enhanced serine phosphorylation of the IRâ suggestive of dysfunctional insulin signaling was observed in cardiac tissues as a result of the treatment. In addition, an enhanced association of both AT1R and AT2R with IRâ was observed in the heart tissue lysates from hypertensive rat heart. To evaluate the tissue effects of Ang II, we compared the transcriptome of hypertensive rat hearts to the controls. Analysis suggests that the Ang II induces multiple responses in heart tissue that result in changes to the gene expression pattern intended to promote insulin sensitivity and insulin resistance. Taken together our results suggest that exogenous Ang II and moderately high salt diet promote metabolic abnormalities in heart tissue that result in sequestration of IR and modulation of IR signaling, and significant changes in gene expression profile in the hypertensive heart.

URI

https://hdl.handle.net/11668/15525

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