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A9953 Telmisartan Inhibits the Autocrine Role of Leptin in Mediating Cardiomyocyte Remodeling in Hypertensive Left Ventricular Hypertrophy Rats through the Angiotensin II–Angiotensin II Type I Receptors and Peroxidase Proliferator-Activated Receptors-G pathways

Objectives: To confirm myocardium autocrine leptin production is involved in stress-overload hypertensive left ventricular hypertrophy, and telmisartan may alleviate myocardial fibrosis and reverse hypertensive left ventricular hypertrophy by inhibiting leptin autocrine function. Methods: Eight-week male Sprague–Dawley (SD) rats (weight:180–230 g) were used to establish the left ventricular hypertrophy model through abdominal aortic constriction. Results: The expression of AngII–AT1R in the myocardial tissue of pressure-overload hypertensive left ventricular hypertrophy rats increased. AngII promotes the nuclear translocation of intracellular activation protein 1 and the synthesis of leptin, as well as leptin release from myocardial tissue through the AT1R–ROS–ERK1/2 pathway. AngII also participates in the imbalance in matrix metalloproteinase (MMP)–tissue inhibitor of metalloproteinase (TIMP) and in the dynamic balance of myocardial extracellular matrix (ECM) collagen synthesis and degradation. The leptin produced by the myocardial-tissue-induced changes in myocardial TGF-&bgr;1/Smad3 and JAK2/STAT3 signaling pathways during stress-overload hypertensive left ventricular hypertrophy promotes myocardial fibrosis through the leptin receptor. Long-term telmisartan treatment reduces myocardial leptin autocrine function by inhibiting the AT1R–ROS–ERK1/2 pathway, as well as restores the MMP/TIMP balance and reverses myocardial fibrosis by stimulating PPAR-&ggr; to inhibit the JAK2/STAT3–TGF-&bgr;1/Smad3 signaling pathway. Conclusion: Hypertensive left ventricular hypertrophy is closely related to the autocrine function of leptin, which is a adipokine in myocardium. A new mechanism for reversing hypertensive left ventricular hypertrophy was discovered and is shown to involve ARB telmisartan with PPAR-&ggr; activation.