2018/01/31 by Mark Nicholls · 1 citation
Biochemistry, Genetics and Molecular Biology · #Hippo pathway signaling and YAP/TAZ
paper · pdf · doi:10.1093/eurheartj/ehx788
openalex publication_date 2018/01/31 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
Dr James T. Willerson, President Emeritus at the Texas Heart Institute, Houston, Texas reveals how his long career in cardiology was triggered by an improbable meeting with one of the great cardiac surgeons Saturday evening: mid-1950s, San Antonio, Texas. Dr Eleanor Willerson, an anaesthesiologist, informs her 14-year-old son James that he is to meet a world-renowned heart surgeon the following morning. A somewhat confused James T. Willerson asks his name. ‘Denton Cooley’, she replies. Despite the clear arrangements, the youthful Willerson remained dubious that Dr Cooley—who was in San Antonio to talk to local physicians after his team had performed their 10 000th heart operation—would have time to speak with him as a teenager. However, the following morning, a station wagon collected him and two other doctors to take them to the San Antonio airport to pick up Dr Cooley and they then drove to one of the physician’s homes. On arrival there, Dr Willerson recalled, ‘one of them stopped Dr Cooley and said, ‘Denton, we want you to meet this young man who is interested in medicine’. ‘I thought, well this is terrific, I do not even have to go inside and take up his time, all I have to do is say hello. It wasn’t that way; he spent 30 min with me’. It was the start of a lifelong friendship and collaboration, which led all the way to the Texas Heart Institute (THI), founded by the world-renowned cardiovascular surgeon in 1962 and dedicated to reducing cardiovascular disease through innovative and progressive programs in research, education and improved patient care. Whilst this meeting shaped Dr Willerson’s interest in cardiology, his mind was already set on a career in medicine. Born in the central Texas town of Lampasas in 1939 about 30 miles from the state capital Austin, he grew up in San Antonio where his mother practised, while his father Dr Darrell Willerson was a General Practitioner. ‘My interest in medicine stems from my parents, not because of anything they asked of me but because I saw the enjoyment they got from helping people’, he said. As a child he would go with his mother when she was called in to the local hospital and also accompany his father on GP house calls. He attended the San Antonio Academy and the Texas Military Institute, leading the Swimming Team to State Championship success before going to the University of Texas (UT) at Austin on a competitive swimming scholarship as a pre-med student. After graduation, he attended Baylor College of Medicine in Houston and renewed his friendship with Denton Cooley, spending the summer in his operating room before going to Massachusetts General Hospital and Harvard Medical School to complete his training in Internal Medicine and Cardiology. In 1972, he was invited to join the UT Southwestern Medical School Faculty and Parkland Hospital in Dallas to help build their cardiology programs, spending 22 years there, and becoming the Chairman of the Cardiology Department and Professor of Medicine. Today, the Chair in Cardiology is named for Dr Willerson at UT Southwestern. In 1989, he was offered the position of Chairman of Internal Medicine at the new UT Houston Medical School, as well as being invited by Dr Cooley to lead the research programs at the THI. In 2001, he was named the President of the University of Texas Health Science Center in Houston which includes Schools of Medicine, Nursing, Dentistry, Public Health, and Graduate Medical Education. He became THI President in 2008 and today is President Emeritus, where he continues to conduct research and see patients. While Dr Cooley has been the significant influence, there are others who have helped shape his career—he refers specifically to Dr Roman Desanctis, Professor of medicine at Massachusetts General Hospital and Dr Edgar Haber at Massachusetts General via his work as a basic scientist working on protein chemistry, as well as Dr Michael De Bakey, the famous heart surgeon at Baylor. A physician scientist for more than half a century, Dr Willerson’s research concentrates on the detection and treatment of unstable atherosclerotic plaques, the discovery of the genes and abnormal proteins responsible for cardiovascular disease and research in the use of stem cells for the repair of hearts and cardiovascular vessels injured by heart attacks. Advances by his team include identification of the role of platelets, the development of the acute coronary syndromes and platelet products. ‘We were the first to show that platelets adhere to injured human plaques in coronary arteries and release several substances, including thromboxane, serotonin, ADP, and others, all of which promote the growth of a thrombus and result in a dynamic narrowing of the injured artery at the site of the injured plaque, which causes a constriction of the artery because of the release of those mediators’, he said. That work has continued from the mid-1970s to the present and been followed by showing that vulnerable atherosclerotic plaques have a temperature heterogeneity resulting from inflammation of the injured plaques, making the plaque unstable and vulnerable to ulceration, fissuring, thrombus development, and a dynamic vasoconstriction. ‘Injury to a plaque with very elevated LDL cholesterol levels and a genetic predisposition attracts macrophages that enter the plaque and release enzymes which cause this inflamed plaque to fissure or ulcerate, a blood clot to form and dynamic vasoconstriction to occur, leading to a heart attack and sometimes sudden death’. The team built catheters that could be positioned close to atherosclerotic plaques in human coronary arteries. This would reveal temperature heterogeneity in inflamed plaques so that part of the plaque is hotter than another part because of the inflammation. This finding helps to identify such a plaque as being at high risk for ulceration or fissuring and developing a thrombus and enhanced vasoconstriction and a myocardial infarction. ‘Subsequently, we have identified the vascular receptor for inflammation and a team working with me at the THI has developed an antagonist of that receptor which can be placed in liposomes and nanoparticles injected into a patient’s vein and attracted to the site of vascular inflammation in vulnerable plaques, which may help identify such a plaque non-invasively by imaging and even blocking the further development of inflammation and serving as a protective treatment’, he added. They expect to identify the vulnerable plaque in humans non-invasively, and that has the potential to treat and stop the progression of the injury to the plaque and subsequent development of a thrombus. Stem cell work and regenerative cardiovascular medicine have been an important research element and his THI group was the first in the world to demonstrate that one could take bone marrow stem cells from a patient and inject them back into the heart with a NOGA catheter and help the injured heart with extensive coronary artery disease and severe heart failure. ‘The tip of the catheter touches the inner wall of the heart, and measures the electrical potential of the site it touches and the velocity of contraction at that segment of the heart that it touches’, he continued. ‘It has a needle can be protruded and withdrawn so one can inject stem cells directly at sites of reversible injury’. Working with Dr Emerson Perin, director of clinical stem cell centre at THI, they were the first to treat humans with severe heart failure and coronary artery disease, where there was no other treatment option, in 2001, in Rio De Janeiro, Brazil. After that success, they petitioned the FDA in the United States to conduct the first American trial with similar patients and similar cells. Further studies showed that it is most effective in people under the age of 60, as with anyone older, the stem cells are often dysfunctional. ‘Subsequently, we have shown that there is a youthful stem cell, mesenchymal stem cell, one can take from bone marrow or from adipose tissue of the young individuals which will be healthy and can be given to an older person and is not rejected and help the severely injured human heart. We have conducted two clinical trials and are into our third and fourth using similar approaches but in one of these trials we are evaluating the combination of a mesenchymal cell and a resident cardiac stem cell, the c-kit cell, in combination and individually, vs. a placebo’. The most recent work published in Nature1 with the leader of the group’s cardiac regenerative medicine team, Dr James Martin, demonstrated reversing heart failure in mice with an experimental heart attack, using an inhibitor of a stop-growth pathway in the mouse heart that allowed regeneration of the heart muscle cells through direct stimulus of these cells. Apart from certain fish, virtually every other species on the planet cannot regenerate their heart if it is injured after about 2 weeks of life, including the human. ‘It turns out that we have a stop growth pathway in our heart that is expressed at about two weeks of life with the unlikely name of the Hippo pathway—a kinase cascade that inhibits the ability of heart muscle cells to regenerate or proliferate’. In the study, the team showed that inhibiting the Hippo pathway through inhibiting the Salvador (Salv) pathway in mouse hearts with established ischaemic heart failure after myocardial infarction promotes regeneration of cardiac muscle cells (i.e. cardiogenesis) from existent heart muscle cells, increases scar border vascularity, reduces fibrosis, and results in the recovery of pumping function of the injured heart compared with controls. ‘The function of the heart improves, blood vessel development is enhanced, and function is improved’, added Dr Willerson. ‘We are very excited about this, it is not a stem cell effect, and this is probably one of the ways that our heart develops’. In his career Dr Willerson has authored more than 1000 scientific articles, 28 textbooks of cardiovascular medicine, holds 15 patents and served for 11 years as the editor of Circulation, the American Heart Association’s journal of cardiovascular medicine, receiving the AHA and ACC Distinguished Scientist Awards. Dr Willerson has a swimming scholarship named in his honour at The UT at Austin and the James T. Willerson Distinguished Chair in Cardiology named after him at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases at The University of Texas Health Science Center at Houston, which he created. He continues to see patients daily and believes that remains important as it gives the physician/scientist a real opportunity to realise what the needs are in cardiovascular medicine. With a keen focus on the training of younger people in cardiology and medicine, advice he gives to young physician scientists and researchers as they set out on a path toward success within the field of cardiovascular medicine is ‘make sure you do it for the right reasons’. ‘If you are going to do this to help others, you will have a very satisfying and special life’, he said. Conflict of interest: none declared.