Aldosterone and not plasminogen activator inhibitor-1 is a critical mediator of early angiotensin II/N-G-nitro-L-arginine methyl ester-induced myocardial injury

Harvard University, Cambridge, Massachusetts, United States
Circulation (Impact Factor: 14.95). 12/2003; 108(20):2517-23. DOI: 10.1161/01.CIR.0000097000.51723.6F
Source: PubMed

ABSTRACT Angiotensin II (Ang II) increases levels of aldosterone and plasminogen activator inhibitor-1 (PAI-1). Both aldosterone and PAI-1 seem to promote cardiovascular (CV) injury. Our objective was to determine the roles of PAI-1 and aldosterone in the development of myocardial and renal damage in a model with high Ang II and low nitric oxide (NO) availability, a pattern seen in patients with heart failure, diabetes mellitus, and arteriosclerosis.
Mice on a moderately high sodium diet were treated with the NO synthase inhibitor NG-nitro-l-arginine methyl ester (L-NAME) for 14 days plus Ang II during days 8 through 14. The roles of aldosterone and PAI-1 in the development of CV injury were assessed using the mineralocorticoid receptor antagonist spironolactone (0, 1.5, 15, and 50 mg x 100 g(-1) x day(-1)) and PAI-1-deficient mice (PAI-1-/-). Ang II/L-NAME-treated mice showed glomerular ischemia, proteinuria, and necrosis of myocytes and vascular smooth muscle cells with an associated mixed inflammatory response, deposition of loose collagen, and neovascularization. Compared with saline-drinking mice, Ang II/L-NAME-treated mice had significantly increased heart to body weight (HW/BW) ratios, cardiac and renal damage assessed by histological examination, PAI-1 immunoreactivity, and proteinuria. Spironolactone treatment decreased PAI-1 immunoreactivity and reduced in a dose-dependent fashion cardiac and renal damage. PAI-1-/- animals had a similar degree of CV injury as PAI-1+/+ animals.
Mineralocorticoid receptor antagonism, but not PAI-1 deficiency, protected mice from developing Ang II/L-NAME-mediated myocardial and vascular injury and proteinuria, suggesting that aldosterone, but not PAI-1, plays a key role in the development of early Ang II/L-NAME-induced cardiovascular injury.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Inhibition of the blood fibrinolytic system (plasminogen/plasmin) occurs either at the level of plasminogen activators, regulated by specific plasminogen activator inhibitors (PAIs) or at the level of plasmin, mainly regulated by alpha 2-antiplasmin (alpha 2-AP). In this contribution, we focused on the roles of alpha 2-AP in acute myocardial infarction and vascular remodeling associated with cardiovascular diseases. Our findings have identified a new target for the development of new therapeutics for the clinical therapy of cardiovascular diseases.
    Letters in Drug Design &amp Discovery 05/2005; 2(3):172-176. DOI:10.2174/1570180053765129 · 0.96 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Reduced coronary flow reserve (CFR), an indicator of coronary microvascular dysfunction, is seen in type 2 diabetes mellitus (T2DM) and predicts cardiac mortality. Since aldosterone plays a key role in vascular injury, the aim of this study was to determine whether mineralocorticoid receptor (MR) blockade improves CFR in individuals with T2DM. Sixty-four men and women with well-controlled diabetes on chronic angiotensin converting enzyme inhibition (enalapril 20 mg/day) were randomized to add-on therapy of spironolactone 25mg, hydrochlorothiazide (HCTZ) 12.5mg, or placebo for 6 months. CFR was assessed by cardiac positron emission tomography (PET) at baseline and at the end of treatment. There were significant and similar decreases in systolic blood pressure with spironolactone and HCTZ but not with placebo. CFR improved with treatment in the spironolactone group as compared with the HCTZ group and with the combined HCTZ and placebo groups. The increase in CFR with spironolactone remained significant after controlling for baseline CFR, change in BMI, race and statin use. Treatment with spironolactone improved coronary microvascular function raising the possibility that MR blockade could have beneficial effects in preventing cardiovascular disease in patients with T2DM.
    Diabetes 08/2014; 64(1). DOI:10.2337/db14-0670 · 8.47 Impact Factor