New Advances on the Biochemical Pathways in the Reninangiotensin System in Hypertension and their role in Cardiac Structure and Function

Cardiovascular disease, including heart failure, remains a leading cause of mortality both in the United States, and worldwide. Two of the most recognized contributing risk factors to the progression of cardiovascular disease and heart failure are hyperension and cardiac hypertrophy. Although the incidence of heart disease has been declining since 1999, it is still the number one killer accounting for 27% of all deaths in the United States in 2005, the latest year for which data are available. Moreover, hypertension is a critical risk factor contributing to cardiac hypertrophy and heart disease, and only about one out of every three patients afflicted with hypertension are actually controlled. Because the renin‐angiotensin system (RAS) plays a major contributing role to the pathophysiology of hypertension and heart disease, the studies outlined in this dissertation traverse the complexities of the biochemical pathways within the cardiac renin‐angiotensin system in normal and hypertensive rats. My research showed first that angiotensin converting enzyme 2 (ACE2) directly converts angiotensin (Ang) II into Ang‐(1‐7) only in hypertrophic hearts isolated from hypertensive rats. Moreover, chronic in vivo pharmacological blockade of ACE2 xvi resulted in a disruption of the balance of cardiac Ang II and Ang‐(1‐7), the result of which was increased cardiac fibrosis and hypertrophy in the absence of functional changes in the heart. In addition, we showed that a new peptide within the biochemical cascade of the RAS — called Ang‐(1‐12) — serves as an alternate substrate for the production of downstream bioactive angiotensin peptides in hearts isolated from norma and hypertensive rats. Collectively, the studies outlined in this dissertation provide newer insights into the complexities that exist within the cardiac RAS. Our data suggest that ACE2 may be a compensatory mechanism in cardiac hypertrophy attempting to overcome for the deleterious ffects of increased cardiac Ang II activity on cardiac remodeling. Furthermore, our data showing that both Ang II and Ang‐(1‐7) are produced from Ang‐(1‐12) in a renin‐independent manner paves the way for the discovery of alternate enzymatic pathways that, in accounting for the generation of angiotensins, may lead to new therapeutic approaches for the treatment of hypertension and heart disease.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2009

Author dc:creator

• Trask, Aaron

• Reninangiotensin system

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10339/14855

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/14855