Thesis (Ph. D.)--University of Adelaide, Dept. of Electrical and Electronic Engineering, 1999? / Includes bibliographical references (leaves 218-228).

Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Biomedical Engineering." Includes bibliographical references (p. 137-144).

Thesis (M.S.)--National Institute of Education, Nanyang Technological University, 2006. / Includes bibliographical references (leaves 77-83).

Thesis (Ph. D.)--Duke University, 2007. / Includes bibliographical references.

Afhandling--Copenhagen.

Thesis (Ph. D.)--University of California, Santa Cruz, 1998. / Typescript. Includes bibliographical references (leaves 429-453).

Afhandling--Copenhagen.

Thesis (M.A.)--University of Wisconsin--Madison, 1968. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M.A.)--University of North Carolina at Chapel Hill, 2002. / Includes bibliographical references (leaves 46-52).

Heart failure (HF) is a pathological state indicating insufficient blood supply to the peripheral tissues from the heart. The pathophysiology of HF is multifactorial like cardiac remodeling including cardiac hypertrophy, perivascular fibrosis and apoptosis to compensate for the heart’s inability to pump enough blood. Cardiac hypertrophy is initially adaptive to hemodynamic overload; however, it chronically contributes to heart failure and sudden cardiac death. The extracellular regulatory factors and intracellular signaling pathways involved in the cardiac remodeling are not yet fully clear. PI3-kinase is an important intracellular kinase in organ size control. Cardiac overexpression of Class I PI3-kinase caused heart enlargement in transgenic mice. Autophagy as a dynamic process involving the degradation of damaged mitochondria prevents ROS overproduction which leads to the cardiac remodeling. Therefore, our aim was to study the relationship between PI3-kinases and Ang II-induced cardiac remodeling via an autophagy-dependent mechanism. Ang II significantly increased autophagy with two distinctive phases: an increasing phase at low doses and a decreasing phase at high doses in cardiomyocytes. The Ang II-induced autophagic depression was attenuated by a Class I PI3-kinase inhibitor and potentiated by Class III PI3-kinase inhibitor. Besides, Ang II-induced cardiac hypertrophy and mitochondria ROS generation were attenuated via blockade of Class I PI3-kinase or mTOR. To further validate our in vitro data, we studied the role of Class I PI3-kinase in Ang II-induced cardiac remodeling in vivo. We successfully transferred Lv-DNp85 (Class I PI3-kinase blockade) and Lv-GFP (control) into adult rat hearts and found that cardiac transfer of Lv-DNp85 did not alter Ang II-induced pressor effect, but attenuated Ang II-induced cardiac hypertrophy, perivascular fibrosis and cardiac dysfunction. Ang II-induced cardiac remodeling was associated with impaired autophagy and mitochondrial ROS overproduction, which were significantly attenuated by Lv-DNp85-induced blockade of Class I PI3-kinase. Taken together, these data suggest that Class I PI3-kinase is involved in Ang II-induced impairment of autophagy via Akt/mTOR pathway, leading to mitochondrial ROS overproduction and cardiac remodeling. These results are not only highly significant from a pathophysiological perspective, but also have important pharmacological implications in the control of cardiac hypertrophy to prevent decompensation and failure in cardiac function. / National Institute of Neurological Disorders and Stroke / National Institutes of Health (NIH, NS55008)