In hypertension, end organ damage (EOD) is due in part to the mechanical forces exerted by high blood pressure (BP);however, other mechanisms such as inflammation, oxidative stress, the RAS, and genetic predisposition, all play key roles in its pathogenesis. In hypertension, Acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), a naturally occurring peptide hydrolyzed mainly by ACE, reduces cardiovascular and renal inflammation and fibrosis without lowering BP. We have evidence that Ac-SDKP mediates some of the anti-fibrotic and anti-inflammatory effects of ACE inh and also prevents experimental autoimmune myocarditis in rats. Thus we propose to test the general hypothesis that in hypertension Ac-SOKP shifts the balance between proinflammatory/ pro-oxidative and anti-inflammatory/anti-oxidative systems in favor of the latter by decreasing innate and adaptive immunity and thus slowing the development of EOD. Furthermore, the effects of Ac-SOKP on BP and EOD are related to the degree of participation of innate and adaptive immunity in the pathogenesis of hypertension and EOD. This hypothesis will be studied in 3 aims.
Aim I : In hypertensive Dahl salt-sensitive rats (Dahl SS) and in mice with systemic lupus erythematosus and hypertension, a model of autoimmune disease, Ac-SDKP acts as an immune modulator, reducing innate and adaptive immunity and thus EOD. Some of the effects of Ac-SDKP depend on the degree of participation of innate and adaptive immunity in the pathogenesis of hypertension and EOD.
Aim II : The effects of ACE inh on the proinflammatory transcription factor NF-kB, T{H} cells and Treg cells are mediated by an increase in Ac-SDKP.
Aim III : The effects of Ac-SDKP are multiphasic;central to these effects are decreases in: 1) the proinflammatory transcription factor NF-KB, 2) differentiation and maturation of dendritic cells (DCs), 3) DC transformation of T cells into effector T cells, and 4) T{H} cell proliferation, activation, migration, and differentiation into pro-inflammatory phenotypes. The effects of Ac-SDKP on T H are partly due to an increase in T{reg} cells. Project I is related to 1) III and IV which also study Dahl SS;2) II and III, which also study the pathogenesis of EOD;and 3) II and IV which also study Ang II. Project I will use all 4 Cores.

Public Health Relevance

Hypertension is a major risk factor for cardiovascular renal morbidity and mortality. If treatment with Ac-SDKP can decrease an over-activation of the immune system and thereby reduce hypertensive EOD in Dahl SS rats, as well as SLE-hyp, it could improve treatment of not only hypertensive EOD but also of other conditions that lead to cardiovascular and renal disease, such as diabetes, autoimmune diseases such as SLE, or even transplant rejection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL028982-31A1
Application #
8460614
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-02-15
Budget End
2014-01-31
Support Year
31
Fiscal Year
2013
Total Cost
$443,416
Indirect Cost
$140,743
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
Gonzalez-Vicente, Agustin; Saikumar, Jagannath H; Massey, Katherine J et al. (2016) Angiotensin II stimulates superoxide production by nitric oxide synthase in thick ascending limbs. Physiol Rep 4:
González, Germán E; Rhaleb, N-E; D'Ambrosio, Martin A et al. (2016) Cardiac-deleterious role of galectin-3 in chronic angiotensin II-induced hypertension. Am J Physiol Heart Circ Physiol 311:H1287-H1296
Ren, Yilin; Janic, Branislava; Kutskill, Kristopher et al. (2016) Mechanisms of Connecting Tubule Glomerular Feedback Enhancement by Aldosterone. Am J Physiol Renal Physiol :ajprenal.00076.2016
Gu, Xiaosong; Xu, Jiang; Zhu, Liping et al. (2016) Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor. Circ Heart Fail 9:
Zhu, Liping; Yang, Xiao-Ping; Janic, Branislava et al. (2016) Ac-SDKP suppresses TNF-α-induced ICAM-1 expression in endothelial cells via inhibition of IκB kinase and NF-κB activation. Am J Physiol Heart Circ Physiol 310:H1176-83
Ramseyer, Vanesa Daniela; Ortiz, Pablo A; Carretero, Oscar A et al. (2016) Angiotensin II-mediated hypertension impairs nitric oxide-induced NKCC2 inhibition in thick ascending limbs. Am J Physiol Renal Physiol :ajprenal.00473.2015
Cerrato, Bruno D; Carretero, Oscar A; Janic, Brana et al. (2016) Heteromerization Between the Bradykinin B2 Receptor and the Angiotensin-(1-7) Mas Receptor: Functional Consequences. Hypertension 68:1039-48
Worou, Morel E; Liao, Tang-Dong; D'Ambrosio, Martin et al. (2015) Renal protective effect of N-acetyl-seryl-aspartyl-lysyl-proline in dahl salt-sensitive rats. Hypertension 66:816-22
Peng, Hongmei; Sarwar, Zeyd; Yang, Xiao-Ping et al. (2015) Profibrotic Role for Interleukin-4 in Cardiac Remodeling and Dysfunction. Hypertension 66:582-9
Monzon, Casandra M; Garvin, Jeffrey L (2015) Nitric oxide decreases the permselectivity of the paracellular pathway in thick ascending limbs. Hypertension 65:1245-50

Showing the most recent 10 out of 376 publications