Hypoxia‐inducible factor‐1α, vascular endothelial growth factor, inducible nitric oxide synthase, and endothelin‐1 expression correlates with angiogenesis in congenital heart disease

Abstract

In Taiwan, the average prevalence of congenital heart disease (CHD) is 13.08/1000 live births. Most children with CHD die before the age of 5 years; therefore, identifying treatment methods to extend the life of CHD patients is an important issue in clinical practice. The objective of this study is to evaluate the roles of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), endothelin-1 (ET-1), and CD34 in CHD autopsy cases in comparison with autopsy cases without CHD. The study included 19 autopsy cases, which were divided into the following four groups: acyanotic CHD (n = 11), cyanotic CHD (n = 3), CHD associated with chromosomal abnormalities (n = 3), and complex CHD (n = 2). Heart specimens obtained from 10 autopsy cases without CHD were included as controls. Our results indicated that high percentages of HIF-1α (100%), VEGF (89.5%), iNOS (78.9%), and ET-1 (84.2%) expressions were observed in CHD autopsy cases and this was found to be significant. HIF-1α induced by hypoxia could play a potential role in relating downstream gene expressions in CHD patients. Upregulation of VEGF by HIF-1α could play an important role in triggering angiogenesis to protect myocardial cell survival in a hypoxic microenvironment. Therefore, HIF-1α could be a significant prognosis marker in CHD and be a prospective candidate in the development of target therapy in cardiovascular diseases.

Healing of Growth Plate Cartilage by Hypoxia Inducible Factor-1α Inhibitor Apigenin on Thiram Induced Tibial Dyschondroplasia

“…This study examined the treatment of TD by natural HIF-1α inhibitor apigenin and the protective effect of this medicine as antioxidant in liver oxidative stress of thiram induced TD birds. HIF-1α is essential for growth and survival of growth plate chondrocytes, while chondrocytes lacking functional HIF-1α have massive cell death in the growth plate which leads to the bone narrow and exhibit less vascularization (Zhang et al, 2012;Yin et al, 2016;Huang et al, 2017b). Previous reports proposed that major regulation of hypoxic responses in chondrogenesis is controlled by HIF-1α (Schipani, 2005).…”

MicroRNAs: pleiotropic players in congenital heart disease and regeneration

“…It was shown, that under hypoxic conditions, HIF-1α (hypoxia-inducible factor-1α) is accumulating rapidly combined with HIF-1β, thus activating downstream genes like VEGF and ET-1 (endothelin-1) which induced proliferation, sprouting and migration of ECs. Especially in patients with cyanotic CHD, consistently elevated HIF-1α levels may induce the development of systemic to pulmonary collateral arteries (95,115,116). However, miR-155 was shown to be down-regulated in patients with VSDs, indicating that VEGF levels were not increased in the cohort and thus did not activate their downstream miRs.…”

“…However, a high number of GUCH patients develop cardiac hypertrophy (CH) (92) and fibrosis (93) in response to altered blood perfusion, abnormal pulmonary pressure or other malformations associated with severe CHDs. Additionally, underdeveloped or abnormal vascularization can trigger severe long-term cardiac complications, including heart failure (94,95). Thus, an adjuvant, miR-based therapeutic option to treat patients facing those problems could be a promising approach to support existing palliative care practices.…”

“…An imbalance of these factors can lead to impaired angiogenesis, also found in patients with CHD (94,95). Therapeutic treatment options in a pro-or anti-angiogenic manner could therefore help to avoid abnormal blood vessel proliferation or enhance normal angiogenic growth within the myocardium of affected patients.…”

“…Regulation of the expression of several miRs was found to be mediated by VEGF, including the modulation of miR-155 and members of the miR-17-92 family such as miR-18a and miR-20a (109). Recently, Yin and colleagues published the correlation of several gene expression patterns of angiogenic genes in CHD, including cases which concomitantly showed hypoxia (95). It was shown, that under hypoxic conditions, HIF-1α (hypoxia-inducible factor-1α) is accumulating rapidly combined with HIF-1β, thus activating downstream genes like VEGF and ET-1 (endothelin-1) which induced proliferation, sprouting and migration of ECs.…”