Persistent accumulation of monocytes/macrophages in the pulmonary artery adventitial/perivascular areas of animals and humans with pulmonary hypertension has been documented. The cellular mechanisms contributing to chronic inflammatory responses remain unclear. We hypothesized that perivascular inflammation is perpetuated by activated adventitial fibroblasts, which, through sustained production of pro-inflammatory cytokines/chemokines and adhesion molecules, induce accumulation, retention, and activation of monocytes/macrophages. We further hypothesized that this pro-inflammatory phenotype is the result of abnormal activity of histone-modifying enzymes, specifically, class I histone deacetylases (HDACs). Methods and Results Pulmonary adventitial fibroblasts from chronically hypoxic hypertensive calves (termed PH-Fibs) expressed a constitutive and persistent pro-inflammatory phenotype defined by high expression of IL-1β, IL-6, CCL2(MCP-1), CXCL12(SDF-1), CCL5(RANTES), CCR7, CXCR4, GM-CSF, CD40, CD40L, VCAM-1. The pro-inflammatory phenotype of PH-Fibs was associated with epigenetic alterations as evidenced by increased activity of HDACs, and the findings that class I HDAC inhibitors markedly decreased cytokine/chemokine mRNA expression levels in these cells. PH-Fibs induced increased adhesion of THP-1 monocytes, and produced soluble factors that induced increased migration of THP-1 and murine bone marrow-derived macrophages (BMDMs), as well as activated monocytes/macrophages to express pro-inflammatory cytokines and pro-fibrogenic mediators (TIMP1 and COL1) at the transcriptional level. Class I HDAC inhibitors markedly reduced the ability of PH-Fibs to induce monocyte/migration and pro-inflammatory activation. Conclusions The emergence of a distinct adventitial fibroblast population with an epigenetically-altered pro-inflammatory phenotype capable of recruiting, retaining and activating monocytes/macrophages characterizes pulmonary hypertension-associated vascular remodeling, and thus could contribute significantly to chronic inflammatory processes in the pulmonary artery wall.
Objective: This study was performed to assess the utility of selective small-molecule inhibitors of class I HDACs in a preclinical model of pulmonary hypertension. Methods and Results:Rats were exposed to hypobaric hypoxia for 3 weeks in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs 1, 2, and 3. The compound reduced pulmonary arterial pressure more dramatically than tadalafil, a standard-of-care therapy for human pulmonary hypertension that functions as a vasodilator. MGCD0103 improved pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced pulmonary arterial pressure in MGCD0103-treated animals was associated with blunted pulmonary arterial wall thickening because of suppression of smooth muscle cell proliferation. Right ventricular function was maintained in MGCD0103-treated animals. Although the class I HDAC inhibitor only modestly reduced right ventricular hypertrophy, it had multiple beneficial effects on the right ventricle, which included suppression of pathological gene expression, inhibition of proapoptotic caspase activity, and repression of proinflammatory protein expression. Key Words: histone deacetylase Ⅲ pulmonary hypertension Ⅲ proliferation Ⅲ gene expression Ⅲ signaling pathways I n patients with pulmonary hypertension (PH), restricted blood flow through the pulmonary arterial circulation due to increased pulmonary vascular resistance often results in right-sided heart failure. Despite recent advances in the treatment of PH, the 5-year mortality rate for individuals with this disease still approaches 50%, which highlights an urgent need for novel therapeutics. 1 Current standards of care for patients with PH typically involve the use of vasoactive drugs, including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins. More effective therapeutic strategies will likely be based on the combined use of vasodilators and agents that target distinct pathogenic mechanisms in PH, such as pulmonary vascular inflammation and fibrosis, as well as aberrant proliferation of smooth muscle cells, endothelial cells, and fibroblasts in the lung vasculature. 2 Additionally, because right ventricular (RV) failure is the cause of death in the majority of PH patients, 3,4 and it is unclear whether standards of care for left ventricular Original received October 8, 2011; revision received January 11, 2012; accepted January 18, 2012. In December 2011 HDACs control cell proliferation, inflammation, and fibrosis by catalyzing removal of acetyl groups from lysine residues in a variety of proteins. The 18 mammalian HDACs are encoded by distinct genes and are grouped into 4 classes. 6 Two broad-spectrum HDAC inhibitors are approved for the treatment of cancer. One of these compounds,...
Abstract-Hypertrophic cardiomyopathy (HCM) is the most common form of sudden death in young competitive athletes.However, exercise has also been shown to be beneficial in the setting of other cardiac diseases. We examined the ability of voluntary exercise to prevent or reverse the phenotypes of a murine model of HCM harboring a mutant myosin heavy chain (MyHC). No differences in voluntary cage wheel performance between nontransgenic (NTG) and HCM male mice were seen. Exercise prevented fibrosis, myocyte disarray, and induction of "hypertrophic" markers including NFAT activity when initiated before established HCM pathology. If initiated in older HCM animals with documented disease, exercise reversed myocyte disarray (but not fibrosis) and "hypertrophic" marker induction. In addition, exercise returned the increased levels of phosphorylated GSK-3 to those of NTG and decreased levels of phosphorylated CREB in HCM mice to normal levels. Exercise in HCM mice also favorably impacted components of the apoptotic signaling pathway, including Bcl-2 (an inhibitor of apoptosis) and procaspase-9 (an effector of apoptosis) expression, and caspase-3 activity. Remarkably, there were no differences in mortality between exercised NTG and HCM mice. Thus, not only was exercise not harmful but also it was able to prevent and even reverse established cardiac disease phenotypes in this HCM model. (Circ Res. 2006;98:540-548.)Key Words: apoptosis Ⅲ exercise Ⅲ hypertrophic cardiomyopathy Ⅲ remodeling T reatment strategies for hypertrophic cardiomyopathy (HCM) depend on clinical symptoms and stratification of sudden death risk with little evidence supporting prophylactic treatment of asymptomatic HCM. 1 It is becoming increasingly evident that cardiac rehabilitation for patients with other forms of cardiac disease such as ischemic heart disease, hypertension, and congestive heart failure (CHF) includes regular exercise, particularly aerobic exercise, and that exercise reduces cardiovascular morbidity and mortality in these subjects. 2,3 Yet there are no reports in the literature that discuss the impact of mild, monitored exercise as a therapeutic measure for HCM patients. Exercise rehabilitation in HCM patients, however, is somewhat counterintuitive considering the high incidence of sudden cardiac death in young athletes and that both the American Heart Association and the European Society of Cardiology strongly encourage preparticipation cardiovascular screening of HCM for young competitive athletes. 4,5 However, we hypothesized that voluntary cage wheel running as a form of mild exercise would improve and/or prevent the pathologic cardiac phenotype in a murine model of HCM. Voluntary cage wheel was chosen as the exercise intervention because it eliminates physical and psychological stressors associated with forced exercise paradigms that may exacerbate the HCM syndrome, and we have previously demonstrated cardiac adaptation to voluntary cage wheel exercise. 6 The particular HCM mouse model developed by our group 7 is ideal to addres...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.