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Activation of signaling molecules and matrix metalloproteinases in right ventricular myocardium of rats with pulmonary hypertension.

Authors: Umar, S  Hessel, M  Steendijk, P  Bax, W  Schutte, C  Schalij, M  Van der Wall, E  Atsma, D  Van der Laarse, A 
Citation: Umar S, etal., Pathol Res Pract. 2007;203(12):863-72. Epub 2007 Oct 29.
Pubmed: (View Article at PubMed) PMID:17913382
DOI: Full-text: DOI:10.1016/j.prp.2007.08.006

Pulmonary hypertension induces right ventricular (RV) overload, which is transmitted to cardiomyocytes via integrins that activate intracellular messengers, including focal adhesion kinase (FAK) and neuronal nitric oxide synthase (NOS1). We investigated whether RV hypertrophy (RVH) and RV failure (RVF) were associated with activation of FAK, NOS1, and matrix metalloproteinases (MMPs). Rats were treated without (RVC) or with a low dose of monocrotaline (30mg/kg) to induce RVH, and with a high dose (80mg/kg) to induce RVF. After approximately 30 days, RV function was determined using a combined pressure-conductance catheter. After sacrifice, FAK, NOS1, their phosphorylated forms (FAK-P and NOS1-P), MMP-2, and MMP-9 were quantified in RV myocardium by immunohistochemistry. In RVH and RVF, RV weight/ body weight increased by 36% and 109%, whereas RV ejection fraction decreased by 23% and 57% compared to RVC, respectively. FAK-P and FAK-P/FAK were highest in RVH (2.87+/-0.12 and 2.52+/-0.23 fold compared to RVC, respectively) and slightly elevated in RVF (1.76+/-0.17 and 1.15+/-0.13 fold compared to RVC, respectively). NOS1-P and NOS1-P/NOS1 were increased in RVH (1.63+/-0.12 and 3.06+/-0.80 fold compared to RVC, respectively) and RVF (2.16+/-0.03 and 3.30+/-0.38 fold compared to RVC, respectively). MMP-2 was highest in RVH and intermediate in RVF (3.50+/-0.12 and 1.84+/-0.22 fold compared to RVC, respectively). MMP-9 was elevated in RVH and RVF (2.39+/-0.35 and 2.92+/-0.68 fold compared to RVC, respectively). Activation of FAK in RVH points to an integrin-dependent hypertrophic response of the myocardium. Activation of NOS1 in failing RV suggests a role of excessive NO in the development of failure and activation of MMPs leading to ventricular remodeling.


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CRRD Object Information
CRRD ID: 5130174
Created: 2011-04-07
Species: All species
Last Modified: 2011-04-07
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.