Pulmonary hypertension (PH) is a devastating disease of diverse etiology that leads to progressive right heart failure and death. It has been proposed that an imbalance between vasoconstrictive and vasodilator mechanisms initiated by pulmonary endothelial dysfunction causes an increased pulmonary vascular remodeling, and fibrosis leading to right ventricular failure and PH. Based on evidence from the literature and our preliminary data, we propose that a balance between endothelial angiotensin converting enzyme (ACE) and ACE2 is critical in maintaining normal pulmonary vascular homeostasis. Thus, an imbalance in ACE/ACE2 is central in the initiation of pathophysiological events leading to PH. We hypothesize that increasing levels of ACE2 or its enzymatic product, Angiotensin-(1-7) [Ang-(1-7)], in the lungs would reverse endothelial dysfunction, decrease pulmonary vascular remodeling, improve right ventricular function and therefore protect and ameliorate or reverse PH. We propose the following aims to support or refute this hypothesis:
Aim 1 will use two additional animal models of PH (hypoxia rat, and bone morphogenetic protein receptor 2, Bmpr2, conditional knockout mouse) to establish the concept that increases in pulmonary ACE2 or Ang-(1-7) would reverse PH.
Aim 2 will test the hypothesis that a newly discovered ACE2 activator, DIZE, would reverse PH. In addition, we will investigate the mechanism of DIZE's actions on the pulmonary vessels.
Aim 3 will investigate the hypothesis that local delivery of ACE2 or Ang-(1-7) by hematopoietic stem cells expressing these therapeutic genes will reverse PH. This multi-disciplinary and physiological genomic approach to investigate the hypothesis that the endothelial ACE/ACE2 is key to the PH pathophysiology is both novel and innovative. In addition, it will: (i) provide evidence that restoration of ACE/ACE2 imbalance in the pulmonary vasculature would reverse PH, and (ii) put us in an outstanding position to translate our hypothesis driven animal investigations into clinical phase trial for PH.

Public Health Relevance

Endothelial dysfunction is one of the early cellular events in the development of cardiopulmonary diseases. Our objective in this investigation is to test the hypothesis that an imbalance in the activities of the vasoconstrictive, proliferative, fibrotic axis (ACEAngII- AT1R) and vasoprotective axis [ACE2-Ang-(1-7)-Mas receptor] of the reninangiotensin system initiates a cascade of signaling events leading to endothelial dysfunction. Thus, restoring a balance by activation of ACE2 or by genetically modified hematopoietic stem cell to deliver ACE2/Ang-(1-7) would orchestrate a robust pulmonary vascular repair and reverse pulmonary hypertension.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL102033-05
Application #
8656391
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Xiao, Lei
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Qi, Yanfei; Raizada, Mohan K (2014) Is natriuretic peptide receptor C a new target for hypertension therapeutics? Hypertension 63:661-2
Hilzendeger, Aline M; Shenoy, Vinayak; Raizada, Mohan K et al. (2014) Neuroinflammation in pulmonary hypertension: concept, facts, and relevance. Curr Hypertens Rep 16:469
Zubcevic, Jasenka; Santisteban, Monica M; Pitts, Teresa et al. (2014) Functional neural-bone marrow pathways: implications in hypertension and cardiovascular disease. Hypertension 63:e129-39
Shenoy, Vinayak; Kwon, Kwang-Chul; Rathinasabapathy, Anandharajan et al. (2014) Oral delivery of Angiotensin-converting enzyme 2 and Angiotensin-(1-7) bioencapsulated in plant cells attenuates pulmonary hypertension. Hypertension 64:1248-59
Qi, Yanfei; Zhang, Juan; Cole-Jeffrey, Colleen T et al. (2013) Diminazene aceturate enhances angiotensin-converting enzyme 2 activity and attenuates ischemia-induced cardiac pathophysiology. Hypertension 62:746-52
Shenoy, Vinayak; Gjymishka, Altin; Jarajapu, Yagna P et al. (2013) Diminazene attenuates pulmonary hypertension and improves angiogenic progenitor cell functions in experimental models. Am J Respir Crit Care Med 187:648-57
Rigatto, Katya; Casali, Karina R; Shenoy, Vinayak et al. (2013) Diminazene aceturate improves autonomic modulation in pulmonary hypertension. Eur J Pharmacol 713:89-93
Fraga-Silva, Rodrigo A; Costa-Fraga, Fabiana P; Murca, Tatiane M et al. (2013) Angiotensin-converting enzyme 2 activation improves endothelial function. Hypertension 61:1233-8
Qi, Yan F; Li, Qiu H; Shenoy, Vinayak et al. (2013) Comparison of the transduction efficiency of tyrosine-mutant adeno-associated virus serotype vectors in kidney. Clin Exp Pharmacol Physiol 40:53-5
Murca, Tatiane M; Almeida, Tatiane C S; Raizada, Mohan K et al. (2012) Chronic activation of endogenous angiotensin-converting enzyme 2 protects diabetic rats from cardiovascular autonomic dysfunction. Exp Physiol 97:699-709

Showing the most recent 10 out of 13 publications