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The Prenatal Renin‐Angiotensin System During a Critical Period in the Development of Hypertensive Heart Disease
Author(s) -
Adetoro Isaiah A,
Lucchesi Pamela Ann,
Cismowski Mary,
Berecek Kathleen,
Bradford Chastity
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1206.10
Subject(s) - endocrinology , medicine , captopril , offspring , renin–angiotensin system , bradykinin , angiotensin ii , plasminogen activator inhibitor 1 , fibrosis , cardiac fibrosis , receptor , downregulation and upregulation , biology , plasminogen activator , blood pressure , pregnancy , genetics , biochemistry , gene
Intrauterine and perinatal maternal stress increase the risk for cardiovascular disease in adult offspring. Upregulation of the renin‐angiotensin‐aldosterone system (RAAS) occurs early in the pathogenesis of hypertension and is associated with the initiation of a pro‐fibrotic myocardial environment. Our previous work with Spontaneously Hypertensive Rats (SHR) demonstrated that short‐term, prenatal and perinatal exposure of SHR dams to the angiotensin converting enzyme inhibitor (ACE1) captopril reduced hypertension and cardiac fibrosis in adult offspring. The goal of this study was to determine if these beneficial are associated with altered maternal imprinting of cardiac RAAS and its pro‐fibrotic targets. Cardiac lysates were prepared from normotensive WKY or SHR male offspring (14 day old) for analysis of RNA (qRT‐PCR) and protein (western blots, enzyme assays) content. AT1R receptor density was assessed by 125 I‐Angiotesin II binding to isolated cardiac fibroblasts. Compared to WKY (n=5, p<0.05), ACE1 mRNA expression, tissue ACE1 activity and AT 1 R receptor density were significantly increased in SHR vs. WKY and were attenuated by maternal captopril treatment. The mRNA expression of anti‐fibrotic ACE2 and bradykinin type 2 receptor were also increased (P< 0.006) in SHR vs. WKY. Interestingly, there were no changes in the expression of other known RAAS targets, including transforming growth factor‐β, (TGF‐β), Col1a, Col3a, or connective tissue growth factor. Compared to WKY, both plasminogen activator inhibitor‐ 1, TGF‐β receptor II protein levels were decreased by ~80% (p<0.01), although mRNA expression was either unchanged or increased (1.32±0.08 fold, P<0.02), respectively. Taken together, these data suggest that in early stages of postnatal development, SHR cardiac RAAS up‐regulation is compensated by down‐regulation of known pro‐fibrotic targets and up‐regulation of the anti‐fibrotic ACE2 and BK 2 R. In conclusion, maternal captopril treatment may alter the epigenetic regulation of genes involved in the development and progression of hypertensive heart disease. Support or Funding Information NIH 2RO1‐HL5604‐12, Research Institute at Nationwide Children's Hospital (PAL) and start‐up funds Tuskegee College (CB)