Alterations of growth factor transcripts in rat lungs during development of monocrotaline-induced pulmonary hypertension

Arcot, Santosh S.; Lipke, David W.; Gillespie, Mark N.; Olson, Jack W.

doi:10.1016/0006-2952(93)90675-m

Cited by 86 publications

(78 citation statements)

References 15 publications

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“…MCT is an endothelial toxin, and a single injection results in endothelial injury selectively in the pulmonary circulation (32), since its active toxic metabolite is secreted by the liver. Endothelial damage results in exposure of PASMCs to circulating growth factors, including PDGF, which is increased early in MCT-PAH, before the rise in PA pressure (33), in agreement with the survivin expression profile ( Figure 2B). Indeed, MCT-PAH can be prevented by prophylactic preservation of the endothelium, where the early endothelial cell loss is prevented by gene transfer of the antiapoptotic angiopoietin-1 at the time of MCT injection (31).…”

Section: Discussionsupporting

confidence: 75%

Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension

McMurtry¹

2005

Journal of Clinical Investigation

337

313

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Pulmonary arterial hypertension (PAH) is characterized by genetic and acquired abnormalities that suppress apoptosis and enhance cell proliferation in the vascular wall, including downregulation of the bone morphogenetic protein axis and voltage-gated K + (Kv) channels. Survivin is an "inhibitor of apoptosis" protein, previously thought to be expressed primarily in cancer cells. We found that survivin was expressed in the pulmonary arteries (PAs) of 6 patients with PAH and rats with monocrotaline-induced PAH, but not in the PAs of 3 patients and rats without PAH. Gene therapy with inhalation of an adenovirus carrying a phosphorylationdeficient survivin mutant with dominant-negative properties reversed established monocrotaline-induced PAH and prolonged survival by 25%. The survivin mutant lowered pulmonary vascular resistance, RV hypertrophy, and PA medial hypertrophy. Both in vitro and in vivo, inhibition of survivin induced PA smooth muscle cell apoptosis, decreased proliferation, depolarized mitochondria, caused efflux of cytochrome c in the cytoplasm and translocation of apoptosis-inducing factor into the nucleus, and increased Kv channel current; the opposite effects were observed with gene transfer of WT survivin, both in vivo and in vitro. Inhibition of the inappropriate expression of survivin that accompanies human and experimental PAH is a novel therapeutic strategy that acts by inducing vascular mitochondria-dependent apoptosis. IntroductionPulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature, defined by an elevated pulmonary vascular resistance (PVR), which eventually leads to right heart failure and premature death. The cause remains unknown, and available treatments are limited, expensive, and often associated with significant side effects (1). In PAH, the pulmonary arteries (PAs) manifest pathological proliferative vascular remodeling that includes cellular proliferation in both the intima and the media and muscularization of the normally thin-walled distal PAs (1). Endothelial dysfunction results in an increase in the ratio of endothelial-derived vasoconstrictors to vasodilators. This imbalance has been the basis of therapies over the past several years; for example, exogenous delivery of vasodilating prostaglandins or blockade of the endothelin axis. However, less that 10% of the patients respond to selective pulmonary vasodilators. While vasoconstriction contributes, especially early in PAH, the obstructive vascular remodeling is the major cause of the elevated PVR and ultimately the right heart failure, which in turn accounts for the 50% 5-year mortality in this disease (1). There is now a shift in the interest of the scientific community, focusing on therapies aiming to reverse the proliferative remodeling in PAH (2).

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Section: Discussionsupporting

confidence: 75%

Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension

McMurtry¹

2005

Journal of Clinical Investigation

337

313

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“…Altered TGF-␤ signaling has also been linked to the vascular pathology of PH, 44 with evidence that PH smooth muscle cells proliferate with TGF-␤ 45 and expression of phosphorylated Smad2/3 (p-Smad2/3; the active form) are increased in remodeled pulmonary arteries. 3 Lungs of schistosomiasis-infected mice showed a significantly increased expression of p-Smad2/3 present in both granulomas and pulmonary arteries in the infected animals ( Figure 5C).…”

Section: Org)mentioning

confidence: 99%

Schistosomiasis-Induced Experimental Pulmonary Hypertension

Graham

Mentink‐Kane

El-Haddad

et al. 2010

The American Journal of Pathology

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The mechanisms underlying schistosomiasis-induced pulmonary hypertension (PH), one of the most common causes of PH worldwide, remain unclear. We sought to determine whether Schistosoma mansoni causes experimental PH associated with pulmonary vascular remodeling in an interleukin (IL)-13-dependent manner. IL-13R␣1 is the canonical IL-13 signaling receptor, whereas IL-13R␣2 is a competitive nonsignaling decoy receptor. Wild-type, IL-13R␣1 ؊/؊ , and IL-13R␣2 ؊/؊ C57BL/6J mice were percutaneously infected with S. ؊/؊ mice. Phosphorylated Smad2/3, a target of transforming growth factor-␤ signaling, was increased in both infected mice and humans with the disease. Our data indicate that experimental schistosomiasis causes PH and potentially relies on up-regulated IL-13 signaling.

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“…Several growth factors, including EGF, PDGF, and TGF-β1, participate in the process of pulmonary vascular remodeling in patients with pulmonary hypertension and in animal models (2,(5)(6)(7)(8). For example, expression of EGF or its receptor EGFR are increased in animal models of monocrotaline-(MCT-) and hypoxia-induced pulmonary hypertension and in humans with pulmonary hypertension (8-10).…”

Section: Introductionmentioning

confidence: 99%

“…Blockade of EGFR results in reductions in pulmonary pressure, right ventricular hypertrophy, and distal arterial muscularization in MCT-induced pulmonary hypertension (11). Moreover, PDGF and its receptor are upregulated in pulmonary arteries of patients with pulmonary hypertension (12,13) and rodents exposed to chronic hypoxia and MCT (7,14,15). PDGF receptor antagonists not only prevent, but also reverse, increased right ventricular pressure and pulmonary vascular changes induced by hypoxia and MCT (13).…”

Section: Introductionmentioning

confidence: 99%

“…Pulmonary vascular remodeling is an important common pathological feature of all categories of pulmonary hypertension. Accumulation of extracellular matrix, including collagen, and vascular smooth muscle cell proliferation and hypertrophy contribute to medial hypertrophy and muscularization, leading to obliteration of precapillary pulmonary arteries and sustained elevation of pulmonary arterial pressure (3, 4).Several growth factors, including EGF, PDGF, and TGF-β1, participate in the process of pulmonary vascular remodeling in patients with pulmonary hypertension and in animal models (2,(5)(6)(7)(8). For example, expression of EGF or its receptor EGFR are increased in animal models of monocrotaline-(MCT-) and hypoxia-induced pulmonary hypertension and in humans with pulmonary hypertension (8-10).…”

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confidence: 99%

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Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease

Han

Greer³

et al. 2011

J. Clin. Invest.

100

105

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Pulmonary hypertension is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling. Several growth factors, including EGF, PDGF, and TGF-β1, are involved in pulmonary vascular remodeling during pulmonary hypertension. However, increased knowledge of the downstream signaling cascades is needed if effective clinical interventions are to be developed. In this context, calpain provides an interesting candidate therapeutic target, since it is activated by EGF and PDGF and has been reported to activate TGF-β1. Thus, in this study, we examined the role of calpain in pulmonary vascular remodeling in two rodent models of pulmonary hypertension. These data showed that attenuated calpain activity in calpain-knockout mice or rats treated with a calpain inhibitor resulted in prevention of increased right ventricular systolic pressure, right ventricular hypertrophy, as well as collagen deposition and thickening of pulmonary arterioles in models of hypoxia-and monocrotaline-induced pulmonary hypertension. Additionally, inhibition of calpain in vitro blocked intracellular activation of TGF-β1, which led to attenuated Smad2/3 phosphorylation and collagen synthesis. Finally, smooth muscle cells of pulmonary arterioles from patients with pulmonary arterial hypertension showed higher levels of calpain activation and intracellular active TGF-β. Our data provide evidence that calpain mediates EGF-and PDGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells via an intracrine TGF-β1 pathway in pulmonary hypertension. IntroductionPulmonary hypertension is a severe and progressive disease characterized by increased pulmonary vascular resistance leading to right heart failure and death (1-3). Pulmonary vascular remodeling is an important common pathological feature of all categories of pulmonary hypertension. Accumulation of extracellular matrix, including collagen, and vascular smooth muscle cell proliferation and hypertrophy contribute to medial hypertrophy and muscularization, leading to obliteration of precapillary pulmonary arteries and sustained elevation of pulmonary arterial pressure (3, 4).Several growth factors, including EGF, PDGF, and TGF-β1, participate in the process of pulmonary vascular remodeling in patients with pulmonary hypertension and in animal models (2,(5)(6)(7)(8). For example, expression of EGF or its receptor EGFR are increased in animal models of monocrotaline-(MCT-) and hypoxia-induced pulmonary hypertension and in humans with pulmonary hypertension (8-10). Blockade of EGFR results in reductions in pulmonary pressure, right ventricular hypertrophy, and distal arterial muscularization in MCT-induced pulmonary hypertension (11). Moreover, PDGF and its receptor are upregulated in pulmonary arteries of patients with pulmonary hypertension (12, 13) and rodents exposed to chronic hypoxia and MCT (7,14,15). PDGF receptor antagonists not only prevent, but also reverse, increased

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Alterations of growth factor transcripts in rat lungs during development of monocrotaline-induced pulmonary hypertension

Cited by 86 publications

References 15 publications

Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension

Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension

Schistosomiasis-Induced Experimental Pulmonary Hypertension

Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease

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