Activation of signaling molecules and matrix metalloproteinases in right ventricular myocardium of rats with pulmonary hypertension.
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.
Umar
Soban
S
Department of Cardiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Hessel
Marleen
M
Steendijk
Paul
P
Bax
Wilhelmina
W
Schutte
Cindy
C
Schalij
Martin
M
van der Wall
Ernst
E
Atsma
Douwe
D
van der Laarse
Arnoud
A
D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D016686:Monocrotaline / Q000633:toxicity; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
D016686:Monocrotaline; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9