Increment of HFABP Level in Coronary Artery In-Stent Restenosis Segments in Diabetic and Nondiabetic Minipigs: HFABP Overexpression Promotes Multiple Pathway-Related Inflammation, Growth and Migration in Human Vascular Smooth Muscle Cells

Abstract

Background: Our previous study suggested that heart-type fatty acid-binding protein (HFABP) levels were greatly elevated in the conditioned medium of explant culture of in-stent restenosis (ISR) tissue from diabetic minipigs compared with those of non-ISR tissue. We here verified this result in animal tissues and investigated the impact of HFABP overexpression in human aortic smooth muscle cells (hASMCs). Methods and Results: In Western blot and real-time RT-PCR, HFABP protein and mRNA levels were significantly higher in ISR than in non-ISR tissues from minipigs, and higher in the ISR tissue from diabetic minipigs than that from nondiabetic minipigs. The mRNA microarray and cellular effects of hASMC retroviral overexpression of HFABP and vector was analyzed.Compared with vector, HFABP transduction activates multiple signaling pathways (e.g. adipokine, TGF-β, Toll-like receptor, Wnt, Hedgehog, ErbB and Notch) and promotes inflammation, growth and migration in hASMCs whereas the knockdown of HFABP by small hairpin RNA attenuates these effects. Conclusion: HFABP expression is significantly higher in ISR tissue than in non-ISR tissue from diabetic and nondiabetic minipigs. Overexpression of HFABP induces multiple pathway-related promotion of inflammation, growth and migration in vascular SMCs, suggesting a potential role in coronary artery ISR.

Role of Hedgehog Signaling in Vasculature Development, Differentiation, and Maintenance

“…These effects are suggested to result from activation of Gli transcription factor directly [139,141,142], from modulation of Notch signaling [48,143,144] or activation of autophagy via Akt, phosphorylation [140]. Besides, Shh promotes SMC and pericyte migration [14,145,146] through ERK1/2 and PI3Kϒ activation [14]. Shh is also proposed either to maintain SMC differentiation [143] or to promote the differentiation of progenitor cells including Sca1+ adventitial resident stem cells [147,148,149] or bone marrow-derived mesenchymal stem cells [136] into SMCs.…”

“…Conversely, Shh, Ptch1, and SMC expression are decreased in aneurysmal tissue samples [143]. At the molecular level, Shh expression in SMCs is increased by hypoxia [139], growth factors such as Pdgf-BB [14,151], heart-type fatty acid-binding proteins [145] and C1q/TNF-related protein-5 [146]. Pdgf-BB-induced Shh expression is shown to depend on ERK1/2 signaling pathway [151].…”

Novel Invasive and Noninvasive Cardiac-Specific Biomarkers in Obesity and Cardiovascular Diseases

“…Additionally, an H-FABP level increased in association with more significant number of cardiovascular risk factors and was an independent risk factor for all causes of cardiovascular death. It is noteworthy that circulating H-FABP concentrations are elevated in NAFLD and metabolic syndrome as well as in obesity, [257][258][259][260][261] signifying that H-FABP is one of the markers of insulin resistance and subclinical myocardial damage that exist in these patients. For this reason, the diagnostic accuracy of H-FABP may make it a useful indicator for the early prediction of high-risk patients in the general population, 244,262 as well as being considered a useful marker for assessing ongoing myocardial damage.…”

Heart-Type Fatty Acid-Binding Protein (H-FABP) and Its Role as a Biomarker in Heart Failure: What Do We Know So Far?

“…survival in human bone marrow derived mesenchymal stem cells in hypoxia [27]. Overexpression of H-FABP promoted growth and migration in human aortic smooth muscle cells [34]. In summary, the precise mechanism by which this protein influences cardiomyocyte proliferation and apoptosis remains elusive and further research is needed to explain its mode of action.…”