Connexin-43 is a promising target for pulmonary hypertension due to hypoxaemic lung disease

Abstract

The mechanisms underlying pulmonary hypertension (PH) are complex and multifactorial, and involve different cell types that are interconnected through gap junctional channels. Although connexin (Cx)-43 is the most abundant gap junction protein in the heart and lungs, and critically governs intercellular signalling communication, its contribution to PH remains unknown. The focus of the present study is thus to evaluate Cx43 as a potential new target in PH.Expressions of Cx37, Cx40 and Cx43 were studied in lung specimens from patients with idiopathic pulmonary arterial hypertension (IPAH) or PH associated with chronic hypoxaemic lung diseases (chronic hypoxia-induced pulmonary hypertension (CH-PH)). Heterozygous Cx43 knockdown CD1 (Cx43+/−) and wild-type littermate (Cx43+/+) mice at 12 weeks of age were randomly divided into two groups, one of which was maintained in room air and the other exposed to hypoxia (10% oxygen) for 3 weeks. We evaluated pulmonary haemodynamics, remodelling processes in cardiac tissues and pulmonary arteries (PAs), lung inflammation and PA vasoreactivity.Cx43 levels were increased in PAs from CH-PH patients and decreased in PAs from IPAH patients; however, no difference in Cx37 or Cx40 levels was noted. Upon hypoxia treatment, the Cx43+/− mice were partially protected against CH-PH when compared to Cx43+/+ mice, with reduced pulmonary arterial muscularisation and inflammatory infiltration. Interestingly, the adaptive changes in cardiac remodelling in Cx43+/− mice were not affected. PA contraction due to endothelin-1 (ET-1) was increased in Cx43+/− mice under normoxic and hypoxic conditions.Taken together, these results indicate that targeting Cx43 may have beneficial therapeutic effects in PH without affecting compensatory cardiac hypertrophy.

Construction and analysis of the abnormal lncRNA–miRNA–mRNA network in hypoxic pulmonary hypertension

“…Some early changes in HPH are difficult to detect with traditional research tools and expertise. Much effort has been afforded to finding new therapeutic targets and biomarkers for HPH (18)(19)(20)(21). Most studies, however, have focused only on mRNAs (18,20,21).…”

Connexin 43 plays a role in proliferation and migration of pulmonary arterial fibroblasts in response to hypoxia

“… 9 , 28 , 29 Conversely, using a C57BL6 mouse model subjected to 14 days of hypoxia, we showed a decrease in Cx43 gene and protein expression in the pulmonary artery, 11 while another study found a 21-day hypoxic exposure to have no effect on CX43 gene expression in the CD1 mouse pulmonary artery. 9 Thus, Cx43 may be differentially regulated by hypoxia depending upon the strain/species as well as the duration of hypoxic exposure. While we may expect a correlation between changes in gene expression and changes in protein expression, this correlation can be as low as 40% in eukaryotes.…”

“…Interestingly, a previous study showed that Cx43 expression was increased in pulmonary arteries from patients with chronic hypoxic PH and that mice heterozygous for Cx43 were protected against hypoxic-induced pulmonary vascular remodelling. 9 Thus, the data presented in this manuscript build on the hypothesis that Cx43 may be a promising therapeutic target for the treatment of PH associated with chronic hypoxia.…”

“…In addition, mice genetically deficient in Cx43 are partially protected against hypoxic-induced PH. 9 Pharmacological inhibition of Cx43 can reduce phenylephrine-induced contraction of pulmonary arteries derived from both chronic hypoxic and monocrotaline rats and also reduce 5-hydroxytryptamine (5-HT)-induced contraction of pulmonary arteries derived from control rats. 10 Mice deficient in Cx43 show reduced pulmonary vascular relaxation, and pharmacological inhibition of Cx43 also reduces pulmonary vascular relaxation.…”

Effect of Aerobic Exercise on Left Ventricular Connexin43 Expression and Distribution in Juvenile and Young Adult Rats

“…Another study on pathological right ventricular cardiac hypertrophy in rats (caused by pulmonary resistance induced hypertension) revealed no increase in Cx43 expression. 40 However, redistributed lateral Cx43 was observed. The increased proportion of lateral Cx43 caused a significant decrease in longitudinal conduction velocity along the cardiomyocytes.…”