We have shown that local angiotensin II (Ang II) production is compartmentalized in the normal heart. Recently, we showed the involvement of the non-angiotensin-converting enzyme (ACE) pathway in regulating blood pressure (BP) in normotensive wild type mice. In contrast, this involvement is not demonstrable in mice with a genetic mast cell (MC) deficiency that causes a loss of Ang ll-forming chymases in the vasculature (Li, et al., J Clin Invest, 114:112-120, 2004). Moreover, we demonstrated that chronic ACE inhibition elevates vascular chymase levels, supporting the contention that chronic ACE inhibitor therapy is limited by up-regulation of the non-ACE pathway. Taken together, these studies have led to the contention that local Ang II production is compartmentalized in both heart and blood vessels. In support of this is the finding that chymase is predominantly in the interstitial space of the vascular adventitia and cardiac interstitial space and in MCs; while ACE is mainly found on the luminal surface of vascular endothelial cells. Importantly, there is increasing evidence that chymase release into the interstitial space is increased from MCs during pathophysiologic stress. Accordingly, we hypothesize that the non-ACE pathway is critical in the development of renovascular hypertension and resultant adverse cardiac and vascular remodeling.
Aim 1 will test the hypothesis that the vascular non-ACE pathway is critically involved in BP regulation by studying differences between MC-sufficient and -deficient mice with chronic renovascular hypertension.
Aim 2 will test the hypothesis that the up-regulation of the non-ACE pathway limits the beneficial effects of ACEi therapy on blood pressure reduction and cardiovascular remodeling in mice with renovascular hypertension.
Aim 3 will test the hypothesis that the vascular and cardiac pathology produced by MC degranulation is principally due to local Ang II production via the non-ACE pathway. The proposed studies are expected to provide new insights into our understanding of how Ang II is formed in blood vessels and the heart and the interplay between ACE and non-ACE tissue Ang ll-generating systems. Such insights will lead to improved therapeutic strategies for the management of cardiovascular diseases.
|Li, Ming; Tejada, Thor; Lambert, Jonathan P et al. (2016) Angiotensin type 2-receptor (AT2R) activation induces hypotension in apolipoprotein E-deficient mice by activating peroxisome proliferator-activated receptor-?. Am J Cardiovasc Dis 6:118-28|
|Tejada, Thor; Tan, Lin; Torres, Rebecca A et al. (2016) IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction. Proc Natl Acad Sci U S A 113:6949-54|
|Naqvi, Nawazish; Singh, Reena; Iismaa, Siiri E et al. (2015) Cardiomyocytes Replicate and their Numbers Increase in Young Hearts. Cell 163:783-4|
|Li, Ming; Iismaa, Siiri E; Naqvi, Nawazish et al. (2014) Thyroid hormone action in postnatal heart development. Stem Cell Res 13:582-91|
|Naqvi, Nawazish; Li, Ming; Calvert, John W et al. (2014) A proliferative burst during preadolescence establishes the final cardiomyocyte number. Cell 157:795-807|
|Calhoun, David A; Booth 3rd, John N; Oparil, Suzanne et al. (2014) Refractory hypertension: determination of prevalence, risk factors, and comorbidities in a large, population-based cohort. Hypertension 63:451-8|
|Zhao, Yu; Bhushan, Shashi; Yang, Chuntao et al. (2013) Controllable hydrogen sulfide donors and their activity against myocardial ischemia-reperfusion injury. ACS Chem Biol 8:1283-90|
|Wasse, Haimanot; Huang, Rong; Naqvi, Nawazish et al. (2012) Inflammation, oxidation and venous neointimal hyperplasia precede vascular injury from AVF creation in CKD patients. J Vasc Access 13:168-74|
|Pisoni, R; Acelajado, M C; Cartmill, F R et al. (2012) Long-term effects of aldosterone blockade in resistant hypertension associated with chronic kidney disease. J Hum Hypertens 26:502-6|
|Acelajado, Maria Czarina; Pisoni, Roberto; Dudenbostel, Tanja et al. (2012) Refractory hypertension: definition, prevalence, and patient characteristics. J Clin Hypertens (Greenwich) 14:7-12|
Showing the most recent 10 out of 20 publications