Laboratory of
Dr. Zam Kassiri
The research in our lab primarily focuses on the contribution of the extracellular matrix (ECM) and its interaction with the resident cells, in cardiac and vascular pathologies. Physiological turnover of the ECM is mediated by matrix metalloproteinases (MMPs) that degrade the existing proteins to be replaced with new proteins, while their activity is kept under control by the inhibitory function of TIMPs (Tissue Inhibitor of Metalloproteinases). TIMPs are a family of 4 members (TIMPs1-4) that collectively inhibit almost all 24 members of the MMP family. In addition to MMPs, some TIMPs can inhibit other proteases such as ADAMs (a disintegrin and metalloproteinases) and ADAM-TSs (ADAM with Thrombospondin motifs) that regulate various cellular events. Reports from our lab and other laboratories have revealed that the ECM does not only provide a structural support for the heart and the vascular tissue (as well as in other organs), but it is a microenvironment for storage of a numerous growth factors and cytokines.
Our lab has been interested in exploring the novel aspects of ECM function in cardiovascular pathologies, for instance, the role of non-fibrillar ECM proteins, novel functions of TIMPs and MMPs, and the contribution of non-MMP proteases in cardiovascular pathologies.
Research Approaches and Models
Our research takes a comprehensive approach which covers the full spectrum of events from molecular and in vitro cellular events to ex vivo organ function and in vivo disease models. We utilize genetically modified mice (knock out, cell specific knockout, and inducible cell-specific Knockout), and animal models of common human cardiovascular diseases such as myocardial infarction/heart attack (by LAD ligation), ischemia-reperfusion (in vivo: temporary LAD ligation), cardiac pressure overload (aortic constriction), hypertrophic and dilated cardiomyopathies, hypertension (Ang II infusion), thoracic and abdominal aortic aneurysm (periadventitial elastase exposure; Ang II infusion in genetically predisposed mice), and atherosclerosis (Ldlr-deficiency + atherogenic diet). Importantly, our access to human heart and aorta specimens has given us the unique opportunity to validate our animal models in human tissue and human cells.
We utilize in vitro culture systems of cardiomyocyes, fibroblasts, vascular smooth muscle cells and endothelial cells (mouse and human) to explore the mechanism of action for the molecules of interest (e.g. TIMPs, MMPs, ADAMs, etc) and to dissect the cell-cell interactions.
Myocardial infarction (MI) and postischemia/reperfusion (I/R) injury
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TIMP2 and MI (Kandalam et al., Circulation Research, 2010);
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TIMP3 and MI (Kandalam et al., American Journal of Physiology: Heart and Circulatory Physiology, 2010);
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TIMP3 and angiogeneis in MI (Takawale et al., American Journal of Physiology: Heart and Circulatory Physiology, 2017);
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TIMP4 and MI (Koskivirta et al., Journal of Biological Chemistry, 2010);
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TIMP4 and I/R injury (Takawale, et al., Circulation: Heart Failure, 2014);
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Cardiomyocyte ADAM17 and MI (Fan et al., Circulation: Heart Failure, 2015).
Pressure overload or agonist-induced hypertension and cardiac hypertrophy
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TIMP1 and myocardial fibrosis in pressure-overload and agonist induced myocardial hypertrophy (Takawale et al., Hypertension, 2017)
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TIMP2 and pressure overload-induced cardiomyopathy (Kandalam et al., Circulation, 2011)
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TIMP3 and pressure overload-induced cardiomyopathy (Kassiri et al., Circulation Research, 2005);
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TIMP2 vs. TIMP3 in myocardial hypertrophy and fibrosis (Fan et al., Cardiovascular Research, 2014);
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TIMP4 and pressure overload-induced cardiomyopathy (Koskivirta et al., Journal of Biological Chemistry, 2010);
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Cardiomyocyte ADAM17 and pressure overload-induced cardiomyopathy (Fan et al., Hypertension, 2016);
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Mechanical unloading of the failing heart and ECM remodeling in patients with dilated cardiomyopathy (Sakamuri et al., Translational Research, 2016);
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Impact of age on ECM remodeling in pediatric and adult heart failure patients;
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Differential role of TIMPs in Ang II-induced hypertension (Basu et al., Cardiovascular Research, 2013);
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Impact of ADAM17-deficiency in smooth muscle cells in Ang II-induced hypertension (Shen et al., Journal of Molecular and Cellular Cardiology, 2017).
Thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA)
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ADAM17-deficiency in smooth muscle cells versus endothelial cells in TAA (Shen et al., Circulation Research, 2018); Folio
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MMP2-deficiency and TAA (Shen et al., Arteriosclerosis, Thrombosis, and Vascular Biology, 2015);
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TIMP3-deficiency increases susceptibility to AAA following Ang II infusion (Basu et al., Journal of Biological Chemistry, 2012); Folio
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Sex-dependent remodeling of the aortic ECM in aneurysmal aorta from patients with bicuspid aortic valves (Lee et al., Journal of Molecular Medicine, 2014).
Lipid metabolism and atherosclerosis
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TIMP4-deficiency and fat metabolism (Sakamuri et al., Scientific Reports, 2017).
Loss of TIMP4 increased plaque accumulation in the abdominal aorta despite lower
plasma cholesterol level.
Hu et al. Artheriosclerosis,Thromb. & Vasc. Biol. (ATVB) 2021
We are extremely grateful to the following agencies for funding our research