Katare Parmeshwar B, Bagul Pankaj K, Dinda Amit K, Banerjee Sanjay K
Drug Discovery Research Center (DDRC), Translational Health Science and Technology Institute (THSTI), Faridabad, India.
Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi, India.
Front Immunol. 2017 Jun 22;8:719. doi: 10.3389/fimmu.2017.00719. eCollection 2017.
Inflammation remains a crucial factor for progression of cardiac diseases and cardiac hypertrophy remains an important cause of cardiac failure over all age groups. As a key regulator of inflammation, toll-like receptor 4 (TLR4) plays an important role in pathogenesis of cardiac diseases. Being an important regulator of innate immunity, the precise pathway of TLR4-mediated cardiac complications is yet to be established. Therefore, the primary objective of the present study was to find the role of TLR4 in cardiac hypertrophy and the molecular mechanism thereof.
Cardiac hypertrophy was induced with administration of isoproterenol (5 mg/kg/day, sc). TLR4 receptor inhibitor RS-LPS (lipopolysaccharide from the photosynthetic bacterium ; 5 μg/day) and agonist lipopolysaccharide (LPS) (from ; 3.12 μg/day) were administered through osmotic pump along with isoproterenol. Cardiac hypertrophy as well as oxidative stress and mitochondrial parameters were evaluated.
Cardiac hypertrophy was confirmed with increased heart weight/body weight ratio as well as assessment of hypertrophic markers in heart. There was a marked increase in the TLR4 expression and oxidative stress along with mitochondrial dysfunction in ISO group. TLR4 inhibition significantly decreased heart weight/body weight ratio and ANP, collagen, and β-MHC expression and restored the disturbed cellular antioxidant flux. The mitochondrial perturbations that were observed in hypertrophy heart was normalized after administration of TLR4 inhibitor but not with the agonist. TLR4 agonism further exaggerated the oxidative stress in heart and hence accelerated the disease development and progression.
Our data show that increased TLR4 ligand pool in cardiac hypertrophy may exaggerate the disease progression. However, inhibition of TLR4 attenuated cardiac hypertrophy through reduced cardiac redox imbalance and mitochondrial dysfunction.
炎症仍然是心脏病进展的关键因素，而心脏肥大是所有年龄段心力衰竭的重要原因。作为炎症的关键调节因子，Toll样受体4（TLR4）在心脏病的发病机制中起重要作用。作为天然免疫的重要调节因子，TLR4介导心脏并发症的确切途径尚未明确。因此，本研究的主要目的是探讨TLR4在心脏肥大中的作用及其分子机制。
通过皮下注射异丙肾上腺素（5mg/kg/天）诱导心脏肥大。将TLR4受体抑制剂RS-LPS（来自光合细菌的脂多糖；5μg/天）和激动剂脂多糖（LPS）（来自；3.12μg/天）与异丙肾上腺素一起通过渗透泵给药。评估心脏肥大以及氧化应激和线粒体参数。
通过增加心脏重量/体重比以及评估心脏中的肥大标志物来确认心脏肥大。ISO组中TLR4表达、氧化应激以及线粒体功能障碍显著增加。TLR4抑制显著降低心脏重量/体重比以及ANP、胶原蛋白和β-MHC的表达，并恢复受干扰的细胞抗氧化通量。给予TLR4抑制剂后，肥大心脏中观察到的线粒体扰动恢复正常，但激动剂未使其恢复正常。TLR4激动作用进一步加剧了心脏中的氧化应激，从而加速了疾病的发展和进展。
我们的数据表明，心脏肥大中TLR4配体库的增加可能会加剧疾病进展。然而，抑制TLR4可通过减少心脏氧化还原失衡和线粒体功能障碍来减轻心脏肥大。
