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)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102033-05
Application #
8656391
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Xiao, Lei
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
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
Cole-Jeffrey, Colleen T; Pepine, Carl J; Katovich, Michael J et al. (2018) Beneficial Effects of Angiotensin-(1-7) on CD34+ Cells From Patients With Heart Failure. J Cardiovasc Pharmacol 71:155-159
Oliveira, Aline C; Sharma, Ravindra K; Aquino, Victor et al. (2018) Involvement of Microglial Cells in Hypoxia-induced Pulmonary Hypertension. Am J Respir Cell Mol Biol 59:271-273
Sharma, Ravindra K; Oliveira, Aline C; Kim, Seungbum et al. (2018) Involvement of Neuroinflammation in the Pathogenesis of Monocrotaline-Induced Pulmonary Hypertension. Hypertension 71:1156-1163
Richards, Elaine M; Raizada, Mohan K (2018) ACE2 and pACE2: A Pair of Aces for Pulmonary Arterial Hypertension Treatment? Am J Respir Crit Care Med 198:422-423
Rathinasabapathy, Anandharajan; Horowitz, Alana; Horton, Kelsey et al. (2018) The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury. Front Physiol 9:180
Richards, Elaine M; Pepine, Carl J; Raizada, Mohan K et al. (2017) The Gut, Its Microbiome, and Hypertension. Curr Hypertens Rep 19:36
Qi, YanFei; Goel, Ruby; Kim, Seungbum et al. (2017) Intestinal Permeability Biomarker Zonulin is Elevated in Healthy Aging. J Am Med Dir Assoc 18:810.e1-810.e4
Raizada, Mohan K; Joe, Bina; Bryan, Nathan S et al. (2017) Report of the National Heart, Lung, and Blood Institute Working Group on the Role of Microbiota in Blood Pressure Regulation: Current Status and Future Directions. Hypertension :
Qi, YanFei; Kim, Seungbum; Richards, Elaine M et al. (2017) Gut Microbiota: Potential for a Unifying Hypothesis for Prevention and Treatment of Hypertension. Circ Res 120:1724-1726
Rathinasabapathy, Anandharajan; Bruce, Erin; Espejo, Andrew et al. (2016) Therapeutic potential of adipose stem cell-derived conditioned medium against pulmonary hypertension and lung fibrosis. Br J Pharmacol 173:2859-79

Showing the most recent 10 out of 38 publications