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Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension.

Kim JD, Lee A, Choi J, Park Y, Kang H, Chang W, Lee MS, Kim J - Exp. Mol. Med. (2015)

Bottom Line: In addition, the susceptibility to PAH has not yet been adequately explained.The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH.This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA.

ABSTRACT
Pulmonary arterial hypertension (PAH) is a rare but progressive and currently incurable disease, which is characterized by vascular remodeling in association with muscularization of the arterioles, medial thickening and plexiform lesion formation. Despite our advanced understanding of the pathogenesis of PAH and the recent therapeutic advances, PAH still remains a fatal disease. In addition, the susceptibility to PAH has not yet been adequately explained. Much evidence points to the involvement of epigenetic changes in the pathogenesis of a number of human diseases including cancer, peripheral hypertension and asthma. The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH. Thus, the pursuit of novel therapeutic targets via understanding the epigenetic alterations involved in the pathogenesis of PAH, such as DNA methylation, histone modification and microRNA, might be an attractive therapeutic avenue for the development of a novel and more effective treatment. This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH.

No MeSH data available.


Related in: MedlinePlus

Proposed multifactorial pathogenesis of pulmonary arterial hypertension (PAH). This figure presents the complex nature of heritable PAH (HPAH) and idiopathic PAH (IPAH). In the case of HPAH, the major driver ‘primary hit' maybe genetic mutation of HPA-associated genes. In many PAH patients, unknown or undetectable ‘secondary hit' mechanisms such as epigenetic alteration, gender and other cardiovascular anomalies, as well as environmental factors, might cooperate in the progression of HPAH. Commonly, IPAH is caused by the combination effect of multiple cues such as non-heritable genetic or epigenetic variations, as well as environmental statuses.
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fig1: Proposed multifactorial pathogenesis of pulmonary arterial hypertension (PAH). This figure presents the complex nature of heritable PAH (HPAH) and idiopathic PAH (IPAH). In the case of HPAH, the major driver ‘primary hit' maybe genetic mutation of HPA-associated genes. In many PAH patients, unknown or undetectable ‘secondary hit' mechanisms such as epigenetic alteration, gender and other cardiovascular anomalies, as well as environmental factors, might cooperate in the progression of HPAH. Commonly, IPAH is caused by the combination effect of multiple cues such as non-heritable genetic or epigenetic variations, as well as environmental statuses.

Mentions: PAH is a complex disease with multiple etiologies and may be mediated by the interplay of genetic background, epigenetic changes and pathobiological environmental factors, which explains the great variability in susceptibility6 (Figure 1). Therefore, the defining molecular mechanisms involved in the pathogenesis of PAH may arise from various aspects due to the multiple etiologies and disease heterogeneity. Emerging evidence has demonstrated the importance of epigenetics in the pathogenesis of PAH.6, 7, 8, 9 Epigenetics is defined as all heritable changes in gene expression that are not related to changes in the underlying DNA sequence.10 To date, the cell-signaling abnormalities, and environmental and genetic mechanisms involved in PAH pathogenesis, have been well studied. However, despite advances in epigenetics technology such as genome-scale DNA methylation analysis, few studies have yet been performed on the epigenetics associated with PAH pathogenesis. The three main types of epigenetic regulation are DNA methylation, histone modification and microRNA (miRNA).11 Although many miRNAs associated with PAH have been elucidated, the involvement of epigenetic regulation via methylation and histone modification in the pathogenesis of PAH remains in critical need of investigation. Our efforts for understanding the initiation and progression of PAH via epigenetics research may provide new insights to identify novel targets for treatment. This review will introduce the current understanding of the epigenetics associated with PAH pathobiology and discuss the possible epigenetic modulations involved in progression of PAH.


Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension.

Kim JD, Lee A, Choi J, Park Y, Kang H, Chang W, Lee MS, Kim J - Exp. Mol. Med. (2015)

Proposed multifactorial pathogenesis of pulmonary arterial hypertension (PAH). This figure presents the complex nature of heritable PAH (HPAH) and idiopathic PAH (IPAH). In the case of HPAH, the major driver ‘primary hit' maybe genetic mutation of HPA-associated genes. In many PAH patients, unknown or undetectable ‘secondary hit' mechanisms such as epigenetic alteration, gender and other cardiovascular anomalies, as well as environmental factors, might cooperate in the progression of HPAH. Commonly, IPAH is caused by the combination effect of multiple cues such as non-heritable genetic or epigenetic variations, as well as environmental statuses.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525299&req=5

fig1: Proposed multifactorial pathogenesis of pulmonary arterial hypertension (PAH). This figure presents the complex nature of heritable PAH (HPAH) and idiopathic PAH (IPAH). In the case of HPAH, the major driver ‘primary hit' maybe genetic mutation of HPA-associated genes. In many PAH patients, unknown or undetectable ‘secondary hit' mechanisms such as epigenetic alteration, gender and other cardiovascular anomalies, as well as environmental factors, might cooperate in the progression of HPAH. Commonly, IPAH is caused by the combination effect of multiple cues such as non-heritable genetic or epigenetic variations, as well as environmental statuses.
Mentions: PAH is a complex disease with multiple etiologies and may be mediated by the interplay of genetic background, epigenetic changes and pathobiological environmental factors, which explains the great variability in susceptibility6 (Figure 1). Therefore, the defining molecular mechanisms involved in the pathogenesis of PAH may arise from various aspects due to the multiple etiologies and disease heterogeneity. Emerging evidence has demonstrated the importance of epigenetics in the pathogenesis of PAH.6, 7, 8, 9 Epigenetics is defined as all heritable changes in gene expression that are not related to changes in the underlying DNA sequence.10 To date, the cell-signaling abnormalities, and environmental and genetic mechanisms involved in PAH pathogenesis, have been well studied. However, despite advances in epigenetics technology such as genome-scale DNA methylation analysis, few studies have yet been performed on the epigenetics associated with PAH pathogenesis. The three main types of epigenetic regulation are DNA methylation, histone modification and microRNA (miRNA).11 Although many miRNAs associated with PAH have been elucidated, the involvement of epigenetic regulation via methylation and histone modification in the pathogenesis of PAH remains in critical need of investigation. Our efforts for understanding the initiation and progression of PAH via epigenetics research may provide new insights to identify novel targets for treatment. This review will introduce the current understanding of the epigenetics associated with PAH pathobiology and discuss the possible epigenetic modulations involved in progression of PAH.

Bottom Line: In addition, the susceptibility to PAH has not yet been adequately explained.The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH.This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, USA.

ABSTRACT
Pulmonary arterial hypertension (PAH) is a rare but progressive and currently incurable disease, which is characterized by vascular remodeling in association with muscularization of the arterioles, medial thickening and plexiform lesion formation. Despite our advanced understanding of the pathogenesis of PAH and the recent therapeutic advances, PAH still remains a fatal disease. In addition, the susceptibility to PAH has not yet been adequately explained. Much evidence points to the involvement of epigenetic changes in the pathogenesis of a number of human diseases including cancer, peripheral hypertension and asthma. The knowledge gained from the epigenetic study of various human diseases can also be applied to PAH. Thus, the pursuit of novel therapeutic targets via understanding the epigenetic alterations involved in the pathogenesis of PAH, such as DNA methylation, histone modification and microRNA, might be an attractive therapeutic avenue for the development of a novel and more effective treatment. This review provides a general overview of the current advances in epigenetics associated with PAH, and discusses the potential for improved treatment through understanding the role of epigenetics in the development of PAH.

No MeSH data available.


Related in: MedlinePlus