Metalloproteinase inhibition protects against cardiomyocyte injury during experimental acute pulmonary thromboembolism.
OBJECTIVE
Up-regulated matrix metalloproteinases may be involved in the development of cardiomyocyte injury and the degradation of troponin associated with acute pulmonary thromboembolism. We examined whether pretreatment with doxycycline (a nonspecific matrix metalloproteinase inhibitor) protects against cardiomyocyte injury associated with acute pulmonary thromboembolism.


METHODS
Controlled animal study.


METHODS
University research laboratory.


METHODS
Mongrel dogs.


METHODS
Anesthetized animals received doxycycline (10 mg/kg intravenously) or saline and acute pulmonary thromboembolism was induced with autologous blood clots injected into the right atrium. Control animals received doxycycline (or saline).


RESULTS
Hemodynamic measurements were performed, and acute pulmonary thromboembolism increased baseline mean pulmonary arterial pressure and pulmonary vascular resistance by approximately 160% and 362%, respectively (both p < .05), 120 mins after acute pulmonary thromboembolism. Pretreatment with doxycycline attenuated these increases (to 125% and 232%, respectively; both p < .05). Although acute pulmonary thromboembolism tended to increase the right ventricle maximum rate of isovolumic pressure development and the maximum rate of isovolumic pressure decay, doxycycline produced no effects on these parameters. Gelatin zymograms of right ventricle showed that acute pulmonary thromboembolism marginally increased matrix metalloproteinase-9 (but not matrix metalloproteinase-2) levels in the right ventricle. A fluorometric assay to assess net matrix metalloproteinase activities showed that acute pulmonary thromboembolism increased matrix metalloproteinase activities in the right ventricle by >100% (p < .05), and this finding was confirmed by in situ zymography of the right ventricle. Doxycycline attenuated acute pulmonary thromboembolism-induced increases in right ventricle matrix metalloproteinase activities. Acute pulmonary thromboembolism induced neutrophil accumulation in the right ventricle, as estimated by myeloperoxidase activity, and doxycycline blunted this effect (p < .05). Serum cardiac troponin I concentrations, which reflect cardiomyocyte injury, increased after acute pulmonary thromboembolism, and this increase was attenuated by pretreatment with doxycycline (p < .05).


CONCLUSIONS
We found evidence supporting the idea that acute pulmonary thromboembolism is associated with increased matrix metalloproteinase activities in the right ventricle, which may lead to degradation of sarcomeric proteins, including cardiac troponin I. Inhibition of matrix metalloproteinases may be an effective therapeutic intervention in the management of acute pulmonary thromboembolism.
Neto-Neves
Evandro M
EM
Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.
Dias-Junior
Carlos A
CA
Rizzi
Elen
E
Castro
Michele M
MM
Sonego
Fabiane
F
Gerlach
Raquel F
RF
Tanus-Santos
Jose E
JE
D000208:Acute Disease; D000704:Analysis of Variance; D000818:Animals; D002302:Cardiac Output; D004195:Disease Models, Animal; D004285:Dogs; D004318:Doxycycline / Q000008:administration & dosage*; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D032383:Myocytes, Cardiac / Q000187:drug effects*; D011655:Pulmonary Embolism / Q000188:drug therapy*; D011897:Random Allocation; D012016:Reference Values; D018709:Statistics, Nonparametric; D019210:Troponin I / Q000097:blood; D018497:Ventricular Dysfunction, Right / Q000473:pathology / Q000517:prevention & control*
D061965:Matrix Metalloproteinase Inhibitors; D019210:Troponin I; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline