TLR Agonists, BCG And Polysacchrides Attenuate Pressure-overload Induced Cardiovascular Hypertrophy And Cardiac Fibrosis By Regulation Of Cardiovascular Immune Microenvironment

Cardiac pressure overload stimulates cardiovascular hypertrophy and cardiac fibrosis, often leading to heart failure. Evidences show that immune responses play an important role in cardiovascular abnomal remodeling. Pressure overload induces to the injures of cardiovascular tissures, which activates pathogen-associated molecular patterns, including Toll-like receptors (TLRs) and non-TLRs, and initiates the innate immune responses. One of the major function of innate immune responses is to activate the adaptive immune response. TLRs are important bridges that connect the innate immune response and the adaptive immune response. It has been proposed that activation of TLRs initiates responses involving helper T cells of the Thl variety, whereas an entirely different class of receptors initiates Th2 responses. Th1 and Th2 cells produce different groups of cytokines, support different immune functions and determine the outcome of tissure injures.We wondered if adjuvant application of TLR agonists and vaccine bacillus Calmette-Guerin (BCG) attenuated pressure overload-induced cardiovascular hypertrophy and cardiac fibrosis. Murine models of hypertension were prepared by suprarenal aortic banding (TAC). Before or after TAC, animals received TLR agonists (10μg/kg/day), IFN-γ(1.5×10~5U/kg/day), BCG(6×10~5CFU/kg/day), or TLR antagonist-msbB(100μg/kg/day) intraperitoneally. TLR2, TLR4 agonist and BCG significantly inhibited TAC-induced cardiovascular hypertrophy and reactive cardiac fibrosis with no changes in hemodynamics. Moreover, TLR4 antagonist revised TLR4 agonist- and BCG-induced actions of anti-cardiovascular hypertrophy and cardiac fibrosis. TLR2 or TLR4 agonist increased the expression of TLR2 or TLR4 on the immune cells infiltrating into the heart tissue, leading to an increased expression ratio of IFN-γ/TGF-βin the hearts. Cardiac protective effects of TLR agonists and BCG related to their regulation of ERK-AKT and p38-NF-κB signaling pathways in the hearts. These results suggested that cardiovascular immune microenvironment plays a critical role in the development of cardiovascular remodeling in hypertension. In conclusion, we find that the activity of TLRs and BCG mediates pressure overload-induced myocardial hypertrophy and fibrosis. TLR agonists and BCG have a great potential for prevention and treatment of hypertension-induced myocardial hypertrophy and cardiac fibrosis.CFX is the fermentative polysaccharides of medical mushroom with potent immune activity. We wonder if CFX can reverse cardiovascular remodeling by regulating cardiac immune microenvironment following pressure overload. After TAC or sham surgery, rats received IFN-γ(1.5×10~5U/kg, i.p.), 0.75 g/kg, 1.5 g/kg or 3.0g/kg of CFX once a day for 28 days. CFX treatment markedly attenuated TAC-induced cardiovascular hypertrophy as well as fibrosis, improved cardiac function, increased expression of TLR4 on the immune cells infiltrating into the heart tissue and promoted the Th1 response which is showed as increasing expression ratio of IFN-γ/TGF-βin hearts. Cardiac protective effects of CFX related to their regulation of TGF-β-Smad/TAK1, ERK-AKT and p38-NF-κB signaling pathways in the hearts. In deed, we confirmed that wortmannin, the inhibitor of PI3K, significantly reversed TAC-induced cardiac hypertrophy and fibrosis with no changes in hemodynamics.