Radiation induces osteogenesis in human aortic valve interstitial cells

Abstract

Objective Irradiation of the chest or chest wall has been shown to caause calcific aortic stenosis. However, the mechanisms are unknown. Aortic valve interstitial cells (AVICs) have been implicated in the pathogenesis of aortic stenosis; they have been shown to change from the phenotype of a myofibroblast to an osteoblast-like cell. We therefore hypothesized that irradiation of human AVICs induces an osteogenic phenotype. In isolated human AVICs, our purpose was to determine the effect of irradiation on the production of osteogenic factors: (a) bone morphogenetic protein-2 (BMP-2) (b) osteopontin (OPN) (c) alkaline phosphatase (ALP), and (d) the transcription factor Runx2. Methods Human AVICs were isolated from normal aortic valves obtained from explanted hearts of patients undergoing cardiac transplantation (n=4) and grown in culture. The cells were grown to confluence, irradiated with 10 Gy using a cesium-137 irradiator and then lysed 24 hours following irradiation. Cell lysates were analyzed via immunoblot and densitometry for BMP-2, OPN, ALP and Runx2. Statistics were by ANOVA. P < 0.05 was significant. Results Irradiation induced an osteogenic phenotype in human AVICs. Irradiation induced a 2-fold increase in BMP-2, a 7-fold increase in OPN, a 3-fold increase in ALP, and a 2-fold increase in Runx2. Conclusions Radiation induces an osteogenic phenotype in human AVICs. The irradiated cells had significantly increased expression of the osteogenic factors BMP-2, OPN, ALP and Runx2. These data offer mechanistic insight into the pathogenesis of radiation-induced valvular heart disease.

Valve Interstitial Cells: The Key to Understanding the Pathophysiology of Heart Valve Calcification

“…In calcified VIC Notch1 sensitizes toll-like receptor 4 to LPS by means of NFjB. 96 Nadlonek, 2012 Human, noncalcified c-Radiation Irradiation of cultured VICs increases osteoblast differentiation. 79 Hutcheson, 2013 Porcine Cadherin-11 Cadherin-11 is activated by TGFb1 via phosphorylation of ERK.…”

“…c-Irradiation of healthy human VICs with 10 Gy induced expression of BMP2, Runx2, osteopontin, and ALP. 96 DNA damage and repair are a routine activities in all cells, but if the balance is tipped toward damage, the cells may undergo apoptosis. Human VICs from sclerotic and stenotic aortic valves have increased oxidative DNA damage compared with the healthy ones, impaired DNA repair enzymes, and decreased expression of superoxide dismutase, catalase, and other antioxidants.…”

Early-Onset Bilateral Severe Valvular Regurgitation After Mediastinal Radiotherapy in Hodgkin Lymphoma Survivors: Should We Screen Prior to 10 Years After Mediastinal Radiotherapy?

“…Another suggestion is that radiation activates an osteogenic phenotype in human aortic valve interstitial cells, leading to increased production of osteogenic factors such as bone morphogenetic protein 2, osteopontin, alkaline phosphatase, and transcription factor RUNX2, which would explain the increased calcification of valves seen in RIV. 16 Risk factors for the development of RIV include dose of radiation, time since treatment, adjuvant anthracycline chemotherapy, and age at presentation. [12][13][14] Understanding the interplay among these factors can help predict the risk of RIV in individual patients.…”

The Onco-cardiologist Dilemma: to Implant, to Defer, or to Avoid Transcatheter Aortic Valve Replacement in Cancer Patients with Aortic Stenosis?

“…The prevalence of AS reaches 16% at 20 years after radiation therapy [33]. This is due to the osteogenic transformation of aortic valve interstitial cells, presumably involved in the pathogenesis of calcific AS [34]. The rate of moderate AS progression in patients with previous mediastinal irradiation is the same as that of matched control patients: 60% of both groups progress to symptomatic severe AS at a mean of 3.6 ± 2 years of follow-up [23].…”