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.
Methods and 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).
Conclusion: 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.