Abstract
Pulmonary arterial hypertension is a debilitating chronic disorder marked by the progressive obliteration of the pre-capillary arterioles. This imposes a pressure overload on the right ventricle (RV) pushing the latter to undergo structural and mechanical adaptations that inexorably culminate in RV failure and death. Thanks to the advances in molecular biology, it has been proposed that some aspects of the RV and pulmonary vascular remodeling processes are orchestrated by a subversion of developmental regulatory mechanisms with an upregulation of a suite of genes responsible for the embryo’s early growth and normally repressed in adults. In this review, we present relevant background regarding the close relationship between overactivation of fetal genes and cardiopulmonary remodeling, exploring whether the reawakening of developmental factors plays a causative role or constitutes a protective mechanism in the setting of PAH.
Highlights
Pulmonary hypertension (PH) represents a heterogeneous group of clinical entities defined as a mean pulmonary artery (PA) pressure above 20 mmHg and subcategorized into five groups by the World Health Organization [1]
Pulmonary arterial hypertension (PAH), which belongs to group 1 PH, is further subdivided into categories depending on the underlying etiologies; idiopathic PAH, heritable PAH, PAH related to various conditions, such as HIV infection, exposure to certain drugs and toxins, connective tissue disease, portal hypertension and congenital heart disease, as well as persistent PH of the newborn [1]
It is tempting to speculate by circular reasoning that pathological narrowing and obliteration of PAs inappropriately reprises feature of early lung development. 2This of 19 is true for right ventricle (RV) hypertrophy in PAH, which is intimately associated with suppression of the postnatal gene program and the concomitant up-regulation of a set of genes operating during cardiac development
Summary
Pulmonary hypertension (PH) represents a heterogeneous group of clinical entities defined as a mean pulmonary artery (PA) pressure above 20 mmHg and subcategorized into five groups by the World Health Organization [1]. Accumulating evidence suggests that these pathological conditions recapitulate the gene expression pattern found in the early developmental stages of the corresponding organ [9,10,11] This is best exemplified by studies conducted in cancer cells demonstrating a reactivation of silent embryonic/fetal genes, normally repressed postnatally, promoting rapid growth of tissues for their own perverse purposes [12,13,14]. It is tempting to speculate by circular reasoning that pathological narrowing and obliteration of PAs inappropriately reprises feature of early lung development This is true for RV hypertrophy in PAH, which is intimately associated with suppression of the postnatal gene program and the concomitant up-regulation of a set of genes operating during cardiac development. From a molecular standpoint, increased activity of the transcription factors cMyc [27] and HIF1α, enhanced expression of glucose transporters (GLUT1 and GLUT4) [26] along with the downregulation of PPARs have been shown to collectively account for the increased glucose uptake, glucose oxidation and repressed FA oxidation [28]
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