Pulmonary Arterial Hypertension

Michelakis, Evangelos D.

doi:10.1161/circresaha.115.301132

Cited by 31 publications

(14 citation statements)

References 25 publications

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“…161,162 Rho-kinase may also be involved in the pathogenesis of PH as it is associated with hypoxic exposure, endothelial dysfunction, VSMC proliferation, enhanced ROS production, and inflammatory cell migration. [163][164][165][166][167][168][169] Chronic exposure to hypoxia induces vascular remodeling in mice. 170 We demonstrated that pulmonary vascular dysfunction plays a crucial role in the development of hypoxia-induced PH, 123,171 for which Rhokinase plays a crucial role.…”

Section: Rho-kinase-mediated Camentioning

confidence: 99%

RhoA/Rho-Kinase in the Cardiovascular System

Shimokawa

Sunamura

Satoh

2016

Circulation Research

370

235

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Twenty years ago, Rho-kinase was identified as an important downstream effector of the small GTP-binding protein, RhoA. Thereafter, a series of studies demonstrated the important roles of Rho-kinase in the cardiovascular system. The RhoA/Rho-kinase pathway is now widely known to play important roles in many cellular functions, including contraction, motility, proliferation, and apoptosis, and its excessive activity induces oxidative stress and promotes the development of cardiovascular diseases. Furthermore, the important role of Rho-kinase has been demonstrated in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, and heart failure. Cyclophilin A is secreted by vascular smooth muscle cells and inflammatory cells and activated platelets in a Rho-kinase–dependent manner, playing important roles in a wide range of cardiovascular diseases. Thus, the RhoA/Rho-kinase pathway plays crucial roles under both physiological and pathological conditions and is an important therapeutic target in cardiovascular medicine. Recently, functional differences between ROCK1 and ROCK2 have been reported in vitro. ROCK1 is specifically cleaved by caspase-3, whereas granzyme B cleaves ROCK2. However, limited information is available on the functional differences and interactions between ROCK1 and ROCK2 in the cardiovascular system in vivo. Herein, we will review the recent advances about the importance of RhoA/Rho-kinase in the cardiovascular system.

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Section: Rho-kinase-mediated Camentioning

confidence: 99%

RhoA/Rho-Kinase in the Cardiovascular System

Shimokawa

Sunamura

Satoh

2016

Circulation Research

370

235

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“…Pulmonary arterial hypertension (PAH) is a fatal disease that is marked by the cancer-like proliferation of pulmonary vascular smooth muscle and endothelial cells. 1 This pathological vascular remodeling leads to occlusion of the precapillary pulmonary arteries, increased pulmonary vascular resistance, right ventricular hypertrophy, and death due to right heart failure within 3 years of diagnosis if left untreated. 2 Germline loss-of-function mutations in BMPR2 —the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor)—have been identified in ≈20% of all PAH cases and over 70% of inherited disease.…”

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confidence: 99%

Endothelial BMPR2 Loss Drives a Proliferative Response to BMP (Bone Morphogenetic Protein) 9 via Prolonged Canonical Signaling

Theilmann

Hawke

Hilton

et al. 2020

ATVB

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Objective: Pulmonary arterial hypertension is a disease of proliferative vascular occlusion that is strongly linked to mutations in BMPR2 —the gene encoding the BMPR-II (BMP [bone morphogenetic protein] type II receptor). The endothelial-selective BMPR-II ligand, BMP9, reverses disease in animal models of pulmonary arterial hypertension and suppresses the proliferation of healthy endothelial cells. However, the impact of BMPR2 loss on the antiproliferative actions of BMP9 has yet to be assessed. Approach and Results: BMP9 suppressed proliferation in blood outgrowth endothelial cells from healthy control subjects but increased proliferation in blood outgrowth endothelial cells from pulmonary arterial hypertension patients with BMPR2 mutations. This shift from growth suppression to enhanced proliferation was recapitulated in control human pulmonary artery endothelial cells following siRNA-mediated BMPR2 silencing, as well as in mouse pulmonary endothelial cells isolated from endothelial-conditional Bmpr2 knockout mice ( Bmpr2 EC −/ − ). BMP9-induced proliferation was not attributable to altered metabolic activity or elevated TGFβ (transforming growth factor beta) signaling but was linked to the prolonged induction of the canonical BMP target ID1 in the context of BMPR2 loss. In vivo, daily BMP9 administration to neonatal mice impaired both retinal and lung vascular patterning in control mice ( Bmpr2 EC+/+ ) but had no measurable effect on mice bearing a heterozygous endothelial Bmpr2 deletion ( Bmpr2 EC+/− ) and caused excessive angiogenesis in both vascular beds for Bmpr2 EC −/− mice. Conclusions: BMPR2 loss reverses the endothelial response to BMP9, causing enhanced proliferation. This finding has potential implications for the proposed translation of BMP9 as a treatment for pulmonary arterial hypertension and suggests the need for focused patient selection in clinical trials.

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“…However, lack of GAG fibers may result in failure of prosthetic valve leaflets. The estimation of glycosaminoglycan content during bioprosthetic valve preparation can be attained by measuring osmotic swelling using a high-frequency ultrasound, which is non-destructive [55][56][57][58][59][60][61].…”

Section: Leafletsmentioning

confidence: 99%

Prosthetic Aortic Heart Valves

Mohammadi¹,

Fradet²

2017

Cardio Vasc Syst

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In this review, the anatomy and structure of the aortic valve and its prostheses are comprehensively discussed. Cardiac anatomy and function, human heart valves and their prostheses are also extensively discussed. The current status of prosthetic heart valves along with the next generation of these devices is broadly deliberated. Ather promising options such astranscatheter technologies (percutaneous valves), minimally invasive techniques, and the construction of prosthetic valves using tissue engineering as futureristic areas of research are brought into conclusion.

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Pulmonary Arterial Hypertension

Cited by 31 publications

References 25 publications

RhoA/Rho-Kinase in the Cardiovascular System

RhoA/Rho-Kinase in the Cardiovascular System

Endothelial BMPR2 Loss Drives a Proliferative Response to BMP (Bone Morphogenetic Protein) 9 via Prolonged Canonical Signaling

Prosthetic Aortic Heart Valves

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