Enhanced postmyocardial infarction fibrosis via stimulation of the transforming growth factor-beta-Smad2 signaling pathway: role of transient receptor potential vanilloid type 1 channels.
OBJECTIVE
To test the hypothesis that the transient receptor potential vanilloid type 1 (TRPV1) channels modulate postmyocardial infarction (MI) fibrosis and matrix formation via the transforming growth factor-beta-Smad signaling pathway to conserve cardiac function and geometrical regeneration.


BACKGROUND
Several lines of evidence indicate that activation of TRPV1 expressed in afferent nerve fibers innervating the heart may preserve cardiac function after MI. However, the underlying mechanisms of TRPV1-mediated protection are largely unknown.


RESULTS
TRPV1-null mutant (TRPV1) and wild-type mice were subjected to left anterior descending coronary ligation or sham operation. Seven days after MI, TRPV1 mice showed an increased infarct size and mortality rate (P < 0.001) when compared with wild-type mice. Enzyme-linked immunosorbent assay analysis showed that transforming growth factor-beta1, vascular endothelial growth factor, and matrix metalloproteinase-2 expression were upregulated to a greater extent in TRPV1 than in wild-type mice after MI (P < 0.001). Western blot showed that Smad2 expression was enhanced in TRPV1 compared with wild-type mice after MI (P < 0.001). Quantitative immunohistochemistry analysis showed that myofibroblast infiltration, capillary density, and collagen content were greater in TRPV1 compared with wild-type mice after MI (P < 0.001), and that the left ventricular lumen was enlarged and the wall thinner in TRPV1 compared with wild-type mice after MI (P < 0.001). Echocardiographic examination showed end-systolic and end-diastolic diameters were increased and the ejection fraction reduced in TRPV1 compared with wild-type mice after MI (P < 0.001).


CONCLUSIONS
Thus, ablation of TRPV1 markedly enhances post-MI fibrosis and impairs myocardial contractile performance, leading to increased propensity of functional heart failure and mortality possibly via stimulation of the transforming growth factor-beta-Smad2 signaling pathway. These data indicate that TRPV1 plays a protective role in MI healing and regeneration.
Huang
Wei
W
Department of Medicine, B316 Clinical Center, Michigan State University, East Lansing, Michigan, USA.
Rubinstein
Jack
J
Prieto
Alejandro R
AR
Wang
Donna H
DH
D000818:Animals; D002196:Capillaries / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020257:Ventricular Remodeling
D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D003094:Collagen; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse