Thrombospondins: A Role in Cardiovascular Disease

Abstract

Thrombospondins (TSPs) represent extracellular matrix (ECM) proteins belonging to the TSP family that comprises five members. All TSPs have a complex multidomain structure that permits the interaction with various partners including other ECM proteins, cytokines, receptors, growth factors, etc. Among TSPs, TSP1, TSP2, and TSP4 are the most studied and functionally tested. TSP1 possesses anti-angiogenic activity and is able to activate transforming growth factor (TGF)-β, a potent profibrotic and anti-inflammatory factor. Both TSP2 and TSP4 are implicated in the control of ECM composition in hypertrophic hearts. TSP1, TSP2, and TSP4 also influence cardiac remodeling by affecting collagen production, activity of matrix metalloproteinases and TGF-β signaling, myofibroblast differentiation, cardiomyocyte apoptosis, and stretch-mediated enhancement of myocardial contraction. The development and evaluation of TSP-deficient animal models provided an option to assess the contribution of TSPs to cardiovascular pathology such as (myocardial infarction) MI, cardiac hypertrophy, heart failure, atherosclerosis, and aortic valve stenosis. Targeting of TSPs has a significant therapeutic value for treatment of cardiovascular disease. The activation of cardiac TSP signaling in stress and pressure overload may be therefore beneficial.

Plasma proteomic signature of the risk of developing mobility disability: A 9‐year follow‐up

“…Thrombospondin‐2 (THBS2) is a 150–160 kDa protein encoded by THBS2 on chromosome 6q27. THBS2 belongs to a group of matricellular proteins that plays a fundamental role in maintaining the architectural continuity of heart and blood vessels (Chistiakov, Melnichenko, Myasoedova, Grechko, & Orekhov, 2017) as well as in cartilage differentiation and prevention of chondrocyte hypertrophy (Jeong et al, 2015). In advanced atherosclerotic lesions, THBS2 stimulates phagocytic function of macrophages, and this activity has been interpreted as anti‐atherogenic (Chistiakov et al, 2017).…”

“…THBS2 belongs to a group of matricellular proteins that plays a fundamental role in maintaining the architectural continuity of heart and blood vessels (Chistiakov, Melnichenko, Myasoedova, Grechko, & Orekhov, 2017) as well as in cartilage differentiation and prevention of chondrocyte hypertrophy (Jeong et al, 2015). In advanced atherosclerotic lesions, THBS2 stimulates phagocytic function of macrophages, and this activity has been interpreted as anti‐atherogenic (Chistiakov et al, 2017). THBS2 gene is overexpressed in response to damage or during remodeling in heart failure, hypertensive cardiac disease, hypertrophic heart (Schroen et al, 2004), and atherosclerosis (Streit et al, 1999) and in the context of these diseases may act as an anti‐angiogenic function (Schroen et al, 2004).…”

“…THBS2 gene is overexpressed in response to damage or during remodeling in heart failure, hypertensive cardiac disease, hypertrophic heart (Schroen et al, 2004), and atherosclerosis (Streit et al, 1999) and in the context of these diseases may act as an anti‐angiogenic function (Schroen et al, 2004). However, the overexpression of THBS2 is considered as an attempt to compensate for the ongoing damage in these pathological conditions although its effectiveness is limited (Chistiakov et al, 2017). An epidemiological study demonstrated that elevated expression of THBS2 gene predicted higher risk of mortality (Shi & Tian, 2019), suggesting high expression of THBS2 marks a condition of risk of health deterioration, although whether it is causally linked to health instability or is a resilience biomarker is not known.…”

Part 1: profiling extra cellular matrix core proteome of human fetal nucleus pulposus in search for regenerative targets

“…This pathway is involved in protein synthesis, inhibition of apoptosis and cell proliferation 37 , these three have shown to play major roles in disc degeneration 8 . Thrombospondins have been identified as a downstream effector protein in this pathway that regulates angiogenesis 38,39 . Interestingly, recent findings have illustrated that maintaining an anaerobe environment is crucial for the functioning of NP cells 40 , thereby highlighting the importance of regulating angiogenesis.…”

Thrombospondin-1 interactions regulate eicosanoid metabolism and signaling in cancer-related inflammation

“…Therefore the bioactive role of these lipid molecules is closely associated to regulation of TSP1 and downstream effects. These complex interactions enable TSP1 to regulate the function of monocytes, macrophages, dendritic cells, T cells, and natural killer cells and profoundly regulate angiogenesis [7–10], all of which play roles in carcinogenesis and metastatic spread.…”