Transforming growth factor β (TGFβ) family members are involved in a wide range of diverse functions and play key roles in embryogenesis, development and tissue homeostasis. Perturbation of TGFβ signaling may lead to vascular and other diseases. In vitro studies have provided evidence that TGFβ family members have a wide range of diverse effects on vascular cells, which are highly dependent on cellular context. Consistent with these observations genetic studies in mice and humans showed that TGFβ family members have ambiguous effects on the function of the cardiovascular system. In this review we discuss the recent advances on TGFβ signaling in (cardio)vascular diseases, and describe the value of TGFβ signaling as both a disease marker and therapeutic target for (cardio)vascular diseases.
The critical role of TGFβ signaling in vascular function was further verified by studies in human. Genetic analysis revealed that mutations in genes of the TGFβ family or genes which affect TGFβ signaling function lead to vascular dysfunction and disease.
It is well appreciated that members of the TGFβ family play a crucial role in the regulation of both normal and abnormal vascular function. TGFβ ligands regulate angiogenesis through their actions either on ECs and/or on mural cells, affecting e.g., proliferation, migration and most importantly cell differentiation, underlying the important role of TGFβ signals in angiogenesis. TGFβ signaling regulates also EC/SMC interactions and by this way further control vascular function.
Missregulation of TGFβ signaling, both in human and mice, leads to vascular dysfunction and vascular pathologies. Recently, it has become evident that TGFβ signaling acts as a rheostat rather than an on-off switch to regulate vascular function. The effects of TGFβ ligands are highly context dependent. Ligand concentration, cell density, cell type, media and culture conditions may determine specific cellular responses to TGFβ family members. In addition the effects of TGFβ signals depend on the interplay between different members of the TGFβ family.
Due to its role in cardiovascular disease pathophysiology, TGFβ signaling components have been considered as potent therapeutic targets in a wide spectrum of cardiovascular disorders.
J Mol Cell Cardiol. 2018 Sep 5;123:75-87. doi: 10.1016/j.yjmcc.2018.08.016. [Epub ahead of print]
Reduction of cardiac TGFβ-mediated profibrotic events by inhibition of Hsp90 with engineered protein.
Myocardial fibroblast activation coupled with extracellular matrix production is a pathological signature of myocardial fibrosis and is governed mainly by transforming growth factor TGFβ-Smad2/3 signaling. Targeting the ubiquitous TGFβ leads to cellular homeostasis deregulation with adverse consequences. We previously showed the anti-fibrotic effects upon downregulation of 90-kDa heat shock protein (Hsp90), a chaperone that associates to the TGFβ signaling cascade. In the present study, we use a fluorescent-labeled Hsp90 protein inhibitor (CTPR390-488) with specific Hsp90 binding properties to reduce myocardial pro-fibrotic events in vitro and in vivo. The mechanism of action involves the disruption of TGFβRI-Hsp90 complex, resulting in a decrease in TGFβ signaling and reduction in extracellular matrix collagen. In vivo, decreased myocardial collagen deposition was observed upon CTPR390-488 treatment in a pro-fibrotic mouse model. This is the first study demonstrating the ability of an engineered Hsp90 protein inhibitor to block collagen expression, reduce the motility of myocardial TGFβ-activated fibroblasts and ameliorate angiotensin-II induced cardiac myocardial fibrosis in vivo.
Cell Physiol Biochem. 2018 Sep 7;49(3):1097-1109. doi: 10.1159/000493293. [Epub ahead of print]
Enhanced Expression of TGFBI Promotes the Proliferation and Migration of Glioma Cells.
Transforming growth factor beta-induced protein (TGFBI) is an extracellular matrix protein induced by TGF-β. Previous studies have reported that the abnormal expression of TGFBI is related to the occurrence and development of some types of cancers, while the role of TGFBI in glioma is uncertain.
The association between TGFBI expression and the prognosis of patients with glioma was analyzed based on data obtained from The Cancer Genome Atlas database. TGFBI expression was analyzed in 3 normal human brains and 57 cases of human gliomas by immunohistochemistry followed by an evaluation of the relationships between TGFBI expression and clinic-pathological features. Furthermore, the RNA interference plasmid pSUPER-shTGFBI was constructed and transfected into U87 and U251 cells to explore the effect of short hairpin RNA against TGFBI (shTGFBI) on cell proliferation, migration, invasion and apoptosis. Western blot analysis was performed to examine the expression of proteins related to apoptosis and proteins in the PI3K/Akt signaling pathway.
High TGFBI expression was found to be associated with poor prognosis in patients with glioblastoma multiforme. Immunohistochemistry showed that TGFBI expression was significantly higher in glioma tissue than in normal human brain tissues. The expression level of TGFBI showed no significant correlation with age, sex, lymph-node metastasis, or pathological grade. sh-TGFBI could inhibit proliferation, invasion and migration and induce apoptosis in U87 and U251 cells in vitro. Furthermore, the phosphorylation levels of AKT and mTOR declined significantly in sh-TGFBI transfected U81 and U251 cells when compared with control.
TGFBI was up-regulated in glioma cells and played a promoting role in the growth and motility of U87 and U251 cells. These results suggested that TGFBI has the potential to be a diagnostic marker and to serve as a target for the treatment of gliomas.
Neurobiological links between depression and AD: the role of TGF-β1 signaling as a new pharmacological target.
Pharmacol Res 2018 Feb 10. Epub 2018 Feb 10.
Department of Drug Sciences, University of Catania, 95125, Catania, Italy; I.B.B., CNR-Catania, Catania, 95125, Italy.
In the last several years a large number of studies have demonstrated the neurobiological and clinical continuum between depression and Alzheimer's disease (AD). Depression is a risk factor for the development of AD, and the presence of depressive symptoms significantly increases the conversion of Mild Cognitive Impairment (MCI) into AD.
Common pathophysiological events have been identified in depression and AD, including neuroinflammation with an aberrant Tumor Necrosis Factor-α (TNF-α) signaling, and an impairment of Brain-Derived Neurotrophic Factor (BDNF) and Transforming-Growth-Factor-β1 (TGF-β1) signaling.
TGF-β1 is an anti-inflammatory cytokine that exerts neuroprotective effects against amyloid-β (Aβ)-induced neurodegeneration, and it has a key role in memory formation and synaptic plasticity.
TGF-β1 plasma levels are reduced in major depressed patients (MDD), correlate with depression severity and significantly contribute to treatment resistance in MDD. The deficit of Smad-dependent TGF-β1 signaling is also an early event in AD pathogenesis, which contributes to inflammaging and cognitive decline in AD. A long-term treatment with antidepressants such as selective-serotonin-reuptake inhibitors (SSRIs) is known to reduce the risk of AD in patients with depression and, SSRIs, such as fluoxetine, increase the release of TGF-β1 from astrocytes and exert relevant neuroprotective effects in experimental models of AD.
** We propose the TGF-β1 signaling pathway as a common pharmacological target in depression and AD, and discuss the potential rescue of TGF-β1signaling by antidepressants as a way to prevent the transition from depression to AD.