Vincent C. Manganiello (1939—2016)

Published June 29 2016

Manganiello was considered the world’s expert on the enzyme PDE3. CAROLINE MANGANIELLO

Vincent C. Manganiello, a pioneer and leader in the field of cyclic nucleotide-mediated signaling, died in January. He was 76.

Vinnie, as he was known to family and friends, was born and raised in Jersey City, N.J. He graduated from two Jesuit schools, Regis High School in New York City and Saint Peter’s College (now Saint Peter’s University) in New Jersey, before attending Johns Hopkins University in Baltimore, where he obtained his Ph.D. in physiological chemistry in 1965 and his M.D. in 1967. A year later, after completing an internship in pediatrics at Johns Hopkins, he accepted a position as a postdoctoral fellow at the National Institutes of Health. He remained there for the rest of his life, eventually becoming chief of the Laboratory of Biochemical Physiology.

From the outset of his career at the NIH, Vinnie studied cyclic nucleotide-mediated signaling. His first papers in the area, co-authored with Ferid Murad and Martha Vaughan at the NIH, described roles for cGMP and cAMP in intracellular signaling in adipocytes (see Murad, F. et al 1970 and Manganiello, V. C. et al 1971). His research moved into the then-new area of cyclic nucleotide phosphodiesterases. In his first paper on the subject, he proposed that hormones could affect cAMP-mediated signaling by modulating the activity of phosphodiesterases. A year later, he showed that the inhibition of lipolysis by insulin in fat cells resulted from a decrease in intracellular cAMP content, which in turn resulted from an increase in the activity of a membrane-associated phosphodiesterase with a high affinity for cAMP. This enzyme, which was later named cyclic GMP-inhibited phosphodiesterase, or cGi-PDE, and finally PDE3, would eventually become the principal focus of his career.

Vinnie’s contributions to his field were many. His laboratory cloned PDE3A and PDE3B, the only two genes identified in this family of phosphodiesterases (see Meacci, E. et al 1992 and Taira, M. et al 1993) to date. He characterized structural determinants of their intracellular distribution (see Kenan, Y. et al 2000 and Shakur, Y. et al 2000) and showed that both PDE3A and PDE3B are regulated by reversible phosphorylation (see Degerman, E. et al 1990 and Smith C. J. 1991). He provided new insight into the mechanisms by which these enzymes are localized to specific intracellular domains by identifying multiprotein signaling complexes in cardiac myocytes and adipocytes to which PDE3A and PDE3B are recruited by phosphorylation in response to various extracellular signals (see Ahmad, F. et al 2007, Ahmad, F. et al 2009, Beca, S et al 2013 and Ahmad, F. et al 2015). He generated PDE3A- and PDE3B-null mice and used these and other models to identify specific roles for each subfamily (see Beca, S. et al 2013, Masciarelli, S. et al 2004, Choi, Y. H., et al 2006 and Chung, Y. W., 2015). Cumulatively, this work contributed enormously to our understanding of the role of PDE3A in regulating contractility in cardiac myocytes and the role of PDE3B in regulating insulin secretion in pancreatic beta cells and metabolism in adipocytes and hepatocytes.

Within the NIH, Vinnie was also known for his citizenship. He contributed 20 years of service on the Institutional Review Board, tasked with review, approval and oversight of human subjects research. According to his colleague Richard Cannon at the NIH, “Vinnie cared deeply about the clear explanation of risks and benefits to research subjects. He insisted that if he couldn’t understand a protocol’s risks, a research subject under considerable stress wouldn’t be able to either. Even when discussions became spirited, he never lost his calm and cheerful demeanor.”

Health problems emerged in the last year and a half of his life. He suffered serious complications after elective surgery on an aortic aneurysm in 2014, but he recovered and published several major papers in 2015. In the summer of 2015 he was diagnosed with pancreatic cancer. He told very few people about his illness and kept working as long as he could. Colleagues were stunned at the news of his death. A recent collaborator at the University of Toronto, Peter Backx, told me, “I had no idea he had been sick. I had just talked with him a few weeks ago about new experiments. He seemed his usual self.” On reflection, those who knew how much he loved research are not surprised that he would keep at it until the very end.

Vinnie was an unassuming man who never craved the spotlight. But his stature in his field is indisputable. When the Gordon Research Conference on Cyclic Nucleotide Phosphodiesterases was initiated in 1999, Vinnie was chosen as its first chairman. He served for many years on the editorial board of the Journal of Biological Chemistry. In 2012, upon his induction into the Johns Hopkins University Society of Scholars, it was noted that he was “internationally recognized for his studies of cyclic nucleotide phosphodiesterases, a multigene family that regulates many fundamental biological processes by controlling intracellular cAMP and cGMP concentrations.” Jackie Corbin, emeritus at Vanderbilt University and a longtime colleague, said, “Vinnie was a wonderful pure scientist and was widely respected as such. He was considered the world’s expert on PDE3, and everyone in this field came to him with questions, requests for materials and suggestions for collaborations. His presence and wisdom at international meetings were critical. He was cheerful and had an outstanding sense of humor. His contributions at a fundamental level are leading to improvements in human health.”

Over his nearly 48-year career at the NIH, Vinnie mentored many people in the phosphodiesterase field and befriended many more in the scientific community. His wife, Caroline, received many letters from Vinnie’s former fellows, who described him as “the best mentor one could ask for,” “a father to young fellows,” “warm and friendly,” “generous with his time and wisdom,” and “selfless.” His character was perhaps best captured by a former fellow who wrote, “(H)e was an example of how scientists should be.” All of these reminiscences are unified in their recognition of his personal decency. For those of us who were privileged to be his colleagues in the scientific community and, even more, his friends, the sorrow at his loss is profound and is tempered only somewhat by our gratitude for the role he was willing to have in our lives.

Matthew Movsesian is a professor of medicine at the University of Utah. He thanks Joel Moss and Eva Degerman for their contributions to this Retrospective.