PHA Pathlight Spring 2014 - (Page 17)

medical professionals research corner Title of Research Article: Adenosine Monophosphate-Activated Protein Kinase is Required for Pulmonary Artery Smooth Muscle Cell Survival and the Development of Hypoxic Pulmonary Hypertension. Authors: Ibe JC, Zhou Q, Chen T, et al. The Question: In pulmonary arterial hypertension (PAH) patients, pulmonary artery smooth muscle cells (PASMC) are resistant to apoptosis, a process of programmed cell death, and proliferate at a faster speed than those in healthy subjects, causing pulmonary artery remodeling and the persistent increase in pulmonary arterial pressure. Although numerous studies suggest that targeting PASMC proliferation may be an effective way to control PAH, little is known about whether regulating the survival of PASMC is an alternative approach to treat PAH. This study attempted to investigate the role of adenosine monophosphate-activated protein kinase (AMPK) in the survival of PASMC, to elucidate the underlying molecular mechanisms, and to explore the role of AMPK inhibitor in the treatment of PAH. Past Studies: AMPK is a serine-threonine protein kinase that consists of three subunits: enzymatic α subunit and regulatory β and γ subunits. It serves as a metabolic sensor for intracellular ATP levels to maintain the cellular energy homeostasis. AMPK is also known to regulate cell survival and proliferation in a cell type specific manner: inhibition of AMPK induces cell death in some cells, whereas in others inhibition of AMPK promotes cell growth and survival. In rapidly proliferating cells such as cardiac fibroblasts and cancer cells, AMPK is activated. In contrast, activation of AMPK actually inhibits proliferation of systemic vascular smooth muscle cells. AMPK is required for the normal lung functions, and abnormal AMPK signaling has been implicated in many lung diseases. This Study: Human PASMC isolated from PAH patients contained elevated AMPK activation and phosphorylation, and hypertensive mice expressed higher AMPK activity than control mice. Exposure to low oxygen (hypoxia), a known stimulus of pulmonary hypertension, increased AMPK activation and phosphorylation, whereas treatment with Compound C, a small molecule inhibitor of AMPK, decreased PASMC survival and induced PASMC death. Human PASMC expressed both α1 and α2 iosforms of AMPK. Inhibition of AMPK α2 alone induced programmed cell death of PASMC by decreasing the expression levels of MCL-1, a protein that helps cell survival. Accordingly, inhibition of MCL-1 also induced programmed cell death of PASMC. Interestingly, inhibition of AMPK α1 alone prevented hypoxia-mediated autophagy, a process of self-breakdown and recycling of cellular components to maintain cellular energy levels to ensure cell survival, causing cell death, independent of programmed cell death. It appears that AMPK α1 and AMPK α2 play distinct yet converging roles in the survival of PASMC: activation of AMPK α2 prevents programmed cell death to promote cell survival, whereas activation of AMPK α1 helps PASMC survive by stimulating autophagy. Administration of Compound C prior to the exposure to hypoxia prevented hypoxia-induced PAH in mice; more importantly, administration of Compound C after the onset of PAH partially reversed the existing PAH. Thus, AMPK is a key player in the initiation and progression of PAH. HEALTH MATTERS Inhibition of AMPK is a Novel Therapeutic Approach for t h e Tr e a t m e n t o f P u l m o n a r y A r t e r i a l H y p e r t e n s i o n Who May Benefit from These Findings? PAH patients, caregivers and the drug discovery community. The Bottom Line: AMPK may represent a novel therapeutic target in the treatment of PAH, and screening for specific AMPK inhibitor is warranted to identify novel therapeutic agents for PAH. Where to Find This Article: American Journal of Respiratory Cell and Molecular Biology 2013; 49(4):609-618. w Reviewed by Guofei Zhou, PhD, and J. Usha Raj, MD, Department of Pediatrics, University of Illinois at Chicago College of Medicine, Chicago, Ill. PATHLIGHT SPRING 2014 Patient-to-Patient Support Line: 1-800-748-7274 17

Table of Contents for the Digital Edition of PHA Pathlight Spring 2014

PHenomenal Lives
Coping with PH
Health Matters
Ask a PH Specialist
Helpful Hints
Research Corner
Advancing the Cause
Support Groups
Special Events
Chapter Happenings
Persistent Voices
Community Classroom
Conference Preview
PHenomenal Youth
Family PHocus

PHA Pathlight Spring 2014