TRPV1 Deficiency Causes Excessive Inflammation, Impairs Wound Healing, And Aggravates Cardiac Remodeling In Mice With Myocardial Infarction

The transient receptor potential vanilloid (TRPV1) subtype is a ligand–gated nonselective cation channel primarily expressed in unmyelinated C or thinly myelinated A-afferent fibers innervating the heart. When TRPV1 is activated or sensitized by proton, bradykinin, or endovanilloids released during myocardial ischemia (MI), it leads to angina. We have previously showed that TRPV1, in addition to its role as a molecule transmitting the pain sensation, preserves cardiac function after ischemia-reperfusion (I/R) injury. However, the underlying mechanisms for TRPV1-mediated cardiac protection are largely unknown. To test the hypothesis that TRPV1 regulates inflammatory process and early remodeling to prevent cardiac functional deterioration after myocardial infarction, TRPV1-null mutant (TRPV1-/-) and wild-type (WT) mice were subjected to left anterior descending coronary ligation or sham operation. The mortality rate, infarct size, inflammatory response, fibrotic changes, and cardiac function were monitored 3 and 7 days post-myocardial infarction. The infarct size on day 3 after MI was bigger in TRPV1-/- than in WT mice (P < 0.001). Levels of plasma cardiac troponin I, infiltration of inflammatory cells including neutrophil and macrophage were significant increased in TRPV1-/- mice. Cytokine including TNF-α, IL-1β, and IL-6, chemokine including MCP-1 and MIP-2 in the infarct area 3 and 7 days after MI were greater in TRPV1-/- than in WT mice (P < 0.05). The mortality rate within 7 days of MI was greater in TRPV1-/- than in WT mice (P < 0.05). Upregulated TGF-βand Smad 2 expression,increased levels of MMP-2 and VEGF, accumulated myofibroblasts deposition and increased collagen content were exhibited in TRPV1-/- mice. Furthermore, increased end-systolic and -diastolic diameters and reduced contractile function of the heart occurred in TRPV1-/- mice, whereas left ventricle geometry and contractility were preserved in WT mice. Thus, our data show that TRPV1 gene deletion results in increased mortality rate, excessive inflammation and collagen deposit, deteriorated cardiac function, and disproportional LV remodeling after MI, indicating that TRPV1 may prevent infarct expansion and cardiac injury by inhibiting inflammation and abnormal tissue remodeling by downregulating TGF-β- Smad signal.