Regulate The Immune Microenvironment Inhibits The Hypertensive Cardiac Hypertrophy And Cardiac Fibrosis

Hypertension-induced chronic cardiac ventricular pressure overload leads to changes in myocardial structure and function that are referred to as myocardial remodeling, consisting of cardiomyocyte hypertrophy and cardiac fibrosis. Apart from the stimulation of neurohormones induced by hypertension, the activation of innate and adaptive immune responses participates in the pathogenesis of cardiovascular remodeling. Molecules of damage associated molecular patterns (DAMPs), which can be actively or passively released to extracellular space after initial damage induced by overload pressure, can ignite innate immune response by activating the pattern recognized receptors. Also this effect will modulate the development of adaptive immune response, especially the balance of Th1/Th2 immune responses which plays critical role in the pathogenesis of cardiac remodeling. We wondered if HSP70, which has been identified as an important molecule of DAMPs, could induce immune response in myocardium and participate in the pathogenesis of hypertension-induced cardiac hypertrophy and fibrosis. Our studies indicated that the sustained pressure overload enhanced the translocation of HSP70 to the membrane of cardiomyocyte and elevated the serum level of HSP70 in the murine model of abdominal aortic constriction (AAC). Inhibition of HSP70 expression by a specific HSP transcription inhibitor reduced the serum level of HSP70 and the abnormal distribution of HSP70 which caused an enhancement of myocardial hypertrophy but a regression of cardiac fibrosis induced by AAC. However, functional blockage of HSP70 by a specific anti-HSP70 antibody significantly attenuated pressure overload-induced cardiac hypertrophy and fibrosis with no changes in hemodynamics. These results indicated that intracellular or extracellular HSP70 mediated the different effects in the regulation of myocardial hypertrophy but only extracellular HSP70 mediated pressure overload-stimulated cardiac fibrosis. The cardiac protective effects of the anti-HSP70 antibody were largely attributed to its capability to block AAC-activated immune response in the heart, which was characterized by increasing infiltrating macrophages and increasing the expression of proinflammatory factor MCP-1 and profibrotic factor TGF-β1. Above results indicated that modulation of abnormal myocardium immune environment may be beneficial to alleviate the pressure overload-inducing cardiac remodeling. Indeed, we also found that BCG, a safe vaccine which strongly promotes Th1 immune response, could attenuate cardiac hypertrophy and fibrosis followed by AAC-induced pressure overload in murine models. BCG prevented cardiac hypertrophy by integrative activation of TLR4 signaling pathway to shift the balance of Th1/Th2 immune responses to Th1 dominant response in the myocardium. The mechanism of this cardiac protective effect was partially due to BCG-induced a decrease in the number of heart infiltrating M2- macrophages.