Our laboratory is involved in understanding the role of inflammatory and metabolic pathways in the progression of cardio-metabolic disorders. Lipids and inflammatory pathways play an important role in the progression of atherosclerotic cardiovascular and metabolic diseases. Monocytes/Macrophages (MMs) are the important components of the human native and acquired immune response (Tiwari RL etal., 2008, Barthwal MK; 2009). Macrophage pattern recognition receptors interact with pathogen-associated molecular patterns resulting in an efficient phagocytic response and an increase in anti-microbial gene expression (Tiwari RL etal., 2008, Barthwal MK; 2009). These cells also interact with T cells through cell-cell and cytokine-mediated interactions to coordinate the evolution of inflammatory response and establish acquired immunity to specific pathogens (Tiwari RL etal., 2008, Barthwal MK; 2009). Although these mechanisms are the main components of the host defence, they are very central to the development of atherosclerotic cardiovascular disease. Pro-inflammatory (M1) and anti-inflammatory (M2) macrophages also play a defining role in adipose tissue inflammation and progression of obesity (Jaiswal A etal., 2018). Recent studies also demonstrate emerging role of macrophages and metabolic pathways in cardiac inflammation (Reddy SS etal., 2018), hypertrophy (Reddy SS etal., 2018) and heart failure (Reddy SS etal., 2018). Hypercholesterolemic mice become extremely resistant to atherosclerosis if they are bred with macrophage-deficient mice (Tiwari RL etal., 2008, Barthwal MK; 2009) and obesity can be reversed by the selectively increasing the adipose tissue alternatively activated macrophage population (Jaiswal A etal., 2018). Cardiac macrophage population and subtype regulate inflammation, cardiac hypertrophy and heart failure. Due to their immense role in innate immune response, lipid uptake and metabolism, foam cell formation, and generation of an inflammatory response during the progression of cardio-metabolic disorders, there is a consensus beyond doubt among various researchers that targeting this cell in cardio-metabolic disorders can yield remarkable results. Overall role of MMs in the progression of cardio-metabolic disorders is evident and understanding their signalling mechanisms will help in the identification of novel drug targets and designing of new therapeutic targets.
Main laboratory findings demonstrate the mechanism of PKC-δ induced IL-1β production in monocytes and macrophages (J Immunol. 2011 Sep 1;187(5):2632-45,) and establish the important role of IRAK-ERK-p67phox-Nox-2 axis in non-sterile inflammation (Cell Mol Immunol. 2016 Nov;13(6):745-763). Findings also demonstrate role of atherogenic lipid oxidized-low density lipoprotein (Ox-LDL) in Interleukin-1 receptor associated kinase, IRAK1,4 activation, sterile inflammation (J Lipid Res. 2014 Jul;55(7):1226-44) and macrophage foam cell formation (Bioessays. 2016 Jul;38(7):591-604). A novel animal model of atherosclerotic cardiovascular disease was developed that showed time dependent increase in hyperlipidemia, vascular dysfunction, inflammation and tendency of thrombosis (J Physiol Biochem. 2011 Jun;67(2):205-16). In the animal model of atherosclerotic cardiovascular disease, IRAK1 mediates vascular smooth muscle cell proliferation and neointimal hyperplasia by regulating PKC-ε-IRAK1-ERK axis and IRAK knock down prevents atherosclerosis progression (ArteriosclerThrombVasc Biol. 2015 Jun;35(6):1445-55). Therefore, IRAK acts as a double-edged sword by preventing inflammation and lipid accumulation, the hallmark features of atherosclerotic cardiovascular disease. In cardio-metabolic disorders resolution of inflammation can be lost due to imbalance between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages. An increase in the adipose tissue pro-inflammatory M1 macrophages often leads to adipose tissue inflammation and obesity. Laboratory demonstrated that in obese mice, microRNA-99a (miR-99a) mimics can regulate macrophage M1 phenotype activation by targeting TNFα. miR-99a therapeutics in diabetic mice reduces the adipose tissue inflammation and improves insulin sensitivity (Cell Mol Immunol. 2018 May 30). These findings speculate the use of miR-99a mimics in diabetes and obesity treatment. It is well established that diabetes and obesity are a predisposing factor for cardiovascular disorders. In studies conducted by the laboratory, Cilastozol ameloriated Angiotensin-II (Ang-II) induced diastolic dysfunction and heart failure with preserved Ejection Fraction (HFpEF) in obese and non-obese mice. Mechanistic studies reveal that the protective effect of Cilostazol on HFpEF can be due to the regulation of inflammatory, fibrotic and metabolic pathways. Cilostazol might be useful in the subset of obese patients with high renin and Ang-II levels (J Mol Cell Cardiol. 2018 Aug 20).
Therefore, laboratory research indicates the important role of inflammation and macrophages in the progression of cardio-metabolic disorders. It also identifies novel signalling mechanisms in relevant disease models and systems that participate in disease progression.
Besides this laboratory also identified novel herbal preparations derived from curcuma longa that prevents high fat diet induced dyslipidaemia, atherosclerosis, insulin resistance and inflammation (Br J Nutr. 2015 Jan 14;113(1):100-13., Br J Nutr. 2013 Aug 28;110(3):437-46, Front Pharmacol. 2016 Jul 25;7:223, Indian J Med Res. 2015 Jun;141(6):823-32) and is in the process of developing a small molecule inhibitor of PCSK9 for preventing atherosclerotic cardiovascular disease.
View More..