Differential hypertensive protease expression in the thoracic versus abdominal aorta
Jean Marie Ruddy, Adam W Akerman, Denise Kimbrough, Elizabeth N Nadeau, Stroud E Robert, Rupak Mukherje, John S Ikonomidis, Jeffrey A Jones
Medical University of South Carolina, Charleston, SC
Background: Hypertension, which is a major risk factor for cardiovascular morbidity and mortality, can drive pathologic remodeling of the macro and micro circulation. Patterns of aortic pathology differ, however, suggesting regional heterogeneity of the pressure-sensitive protease systems triggering extracellular matrix remodeling in the thoracic (TA) and abdominal aortas (AA). This study tested the hypothesis that the expression of two major protease systems (matrix metalloproteinases (MMPs), and cathepsins) in the TA and AA would be differentially affected with hypertension.
Methods: Normotensive (BPN/3) mice at 14-16 weeks of age underwent implantation of osmotic infusion pumps for 28 day Angiotensin II (BPN/3+AngII; n=3) delivery (1.46mg/kg/day) to induce hypertension. The TA and AA were harvested to determine levels of MMP-2, MMP-9, MT1-MMP, and cathepsins S, K, and L were evaluated in age matched BPN/3 (n=8) control and BPH/2 spontaneously hypertensive mice (non-AngII pathway; n=4). Blood pressure was monitored via CODA tail plethysmography. Quantitative RT-PCR and immunoblotting/zymography was used to measure MMP and cathepsin mRNA expression and protein abundance, respectively. All values in the hypertensive mice were compared using a one sample t-test to control mice. In addition comparisons between the BPN/3+AngII and BPH/2 were made using a two sample t-test.
Results: Following 28 days infusion, the BPN/3+AngII mice had a 17% increase in systolic blood pressure, matching that of the BPH/2 spontaneously hypertensive mice (both p<0.05 vs. control BPN/3). MMP-2 mRNA levels were elevated in TA and AA in BPH/2 as well as BPN/3+AngII mice, but was further elevated in the TA of BPN/3+AngII mice with concordant increase in zymographic abundance (p<0.05). MMP-9 mRNA was decreased in the TA of BPH/2 mice and in the AA of both experimental groups (p<0.05 vs. control). MT1-MMP mRNA trended up in the TA and down in the AA in both hypertensive models. Expression of cathepsins K and L was reduced in both aortic regions of BPH/2 mice (p<0.05), with concordantly decreased protein abundance in the AA (p<0.05). However, mRNA levels of cathepsins S, K, and L were increased in the TA of BPN/3+AngII mice compared to normotensive control (p<0.05).
Conclusions: By utilizing two different models of hypertension, this study has identified pressure-dependent as well as AngII-dependent regional alterations in aortic gene expression of MMPs and cathepsins that may lead to differential remodeling responses in each of the aortic regions. Further studies will delineate mechanisms and may provide targeted therapies to attenuate down-stream aortic pathology based on demonstrated regional heterogeneity.
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