Vincent Manganiello earned his Ph.D. and M.D. from Johns Hopkins University in 1965 and 1967, respectively. He joined the NHLBI after his internship from 1967 to 1968 at the Harriet Lane Pediatric Service at Johns Hopkins Hospital. In 2010 he became a Senior Investigator and Chief of the Laboratory of Biochemical Physiology (CPB). A member of the NHLBI institutional review board, he also serves on the editorial boards of the Journal of Biological Chemistry and CHEST. Dr. Manganiello received the NIH Public Health Service Special Recognition Award in 1991, the NIH Director's Award in 1994, a NIH Bench to Bedside Award in 2003, and the Excellence in Sarcoidosis Research Award at the 2005 American Thoracic Society Meeting. He was admitted into the Johns Hopkins University Society of Scholars in 2012. He has authored or coauthored more than 220 papers and book chapters. He is also a member of the American Society of Molecular and Biological Chemists, American Thoracic Society, American Diabetes Association, and American College of Chest Physicians.
Cells use a variety of molecular messengers to turn signals that impinge on their surfaces into appropriate actions. The cyclic nucleotides cAMP and cGMP are important intracellular messengers that are critical in the transduction of many hormonal signals, including insulin. For these cellular signals to be effective within rapid time scales, however, their controlled destruction is as important as their activation. Dr. Manganiello studies cyclic nucleotide phosphodiesterases (PDEs), which catalyze the hydrolysis of cAMP and cGMP, and thereby regulate their intracellular concentrations and biological effects. PDEs comprise a large and complex superfamily, composed of 11 gene families (PDEs 1-11), which are structurally related but exhibit specific functions. Having first isolated, purified, and characterized a PDE that was activated by insulin and played a critical role in the anti-lipolytic effects of insulin, he and his colleagues characterized it as a member of the PDE3 gene family.
Dr. Manganiello’s laboratory focuses on the PDE3 gene family, which contains two subfamilies, PDE3A and PDE3B. The first to clone and characterize their associated cDNAs, Dr. Manganiello’s laboratory then generated PDE3A and PDE3B knockout mice. He and his colleagues are using these models as well as cell culture techniques to study specific roles of PDE3A and PDE3B in regulating important biological processes. They also utilize state-of-the-art molecular and cellular biology techniques to elucidate mechanisms for intracellular localization and membrane association of PDE3 isoforms, as well as to identify signaling pathways, interacting partners, and structural determinants involved in their covalent modification, activation, and regulation.
Dr. Manganiello’s laboratory has contributed to understanding roles played by PDE3A in regulation of platelet aggregation, myocardial contractility, and vascular tone. He and his colleagues have also shown that PDE3A-deficient female mice are infertile and that PDE3A is essential for maturation of oocytes and their capacity for fertilization. More recently, they reported that PDE3A, not PDE3B, regulates cAMP-mediated inhibition of proliferation of vascular smooth muscle cells, and that as a component of a macromolecular regulatory complex or “signalosome” that contains the sarcoplasmic reticulum (SR) calcium ATPase (SERCA) pump, PDE3A regulates cAMP-activated calcium uptake into the SR and, consequently, myocardial contractility.
Dr. Manganiello and his colleagues have shown that PDE3B is important in the regulation of energy homeostasis, especially insulin secretion, the anti-lipolytic action of insulin, and other effects of insulin on fat and sugar metabolism. In PDE3B knockout mice white adipose tissue (WAT) expresses fewer pro-inflammation markers than wild type WAT, and activation of the NLRP3 inflammasome (which is associated with development of obesity) is reduced in knockout WAT. PDE3B knockout WAT also takes on characteristics of metabolically favorable and “healthy” brown fat (BAT), which may be of clinical relevance, in that conversion of fat-storing WAT to fat-burning BAT may represent a potential strategy for treatment of obesity and diabetes.
Moving from bench to bedside, Dr. Manganiello has pursued translational research studies, attempting to develop novel alternatives to prednisone as therapy for pulmonary sarcoidosis (an inflammatory disease that can affect nearly any part of the body and progress to irreversible lung damage in certain patients). Because of the known inhibitory effects of cAMP and PDE inhibitors on various inflammatory responses and the presence of PDEs in immune/inflammatory cells, his laboratory evaluated PDE inhibitors as possible therapy in pulmonary sarcoidosis. In collaboration with colleagues, he reported that the PDE inhibitor pentoxifylline reduced episodes of disease recurrence in a small group of subjects. The results of this trial, coupled with continued basic and translational research, could open up new avenues for PDE-associated therapies.