Prof Huang Yu: nitric oxide and cardiovascular diseases

15 November 2017

Professor Huang Yu's recent research focused on endothelial cells and their dysfunction in a close link with hypertension, obesity and diabetes.

Professor Huang Yu (Croucher Senior Research Fellowship 2014) is Professor of School of Biomedical Sciences at Chinese University of Hong Kong (CUHK) and is a recognised international expert in research of vascular biology and pharmacology. His current research is primarily focused on endothelial cells (those that form the inner lining of blood vessels) and their dysfunction in a close link with hypertension, obesity and diabetes.

His laboratory specifically investigates endothelial dysfunction and seeks to develop ways to reverse vascular dysfunction in animal models of cardio-metabolic diseases.

Huang was born in rural Fujian province and it was when his father arranged for him to study part-time with a Traditional Chinese Medicine (TCM) practitioner as a teenager, that his interest in pharmacology, herbs and human biology was first triggered.

After performing well in the national exams, Huang won one of only five places allocated to students from Fujian province to study pharmacology at Shanghai First Medical College, China (Fudan University Shanghai Medical College since 2002).

“There was no internet and no mobile phones- we were all very much focused on our studies and only moved around between the classroom, dormitory and canteen,” remembers Huang who found that there was very little information about scientific development abroad, so he spent many hours reading English language journals in the university library.

“By year three I started to think I needed to study abroad,” he says explaining that in China the quality of research and the research environment was still quite poor in 1980s and the few teachers who had studied overseas seemed very enlightened.

Huang made a formal application and after a few offers from universities in the UK and USA, decided to accept a place at the University of Cambridge but armed with only basic English language skills, initially found the transition quite challenging.

“My PhD supervisor at Cambridge was Dr Graeme Henderson and he was from Glasgow area and had a broad Scottish accent which at first, I couldn’t really understand,” he says.

At Cambridge, he mostly worked in the field of neuroscience on how a hormone called angiotensin II affected central adrenergic function. After the award of his PhD, Huang started to consider further studies overseas and opted to undertake post-doctoral training at the University of Vermont.

It proved to be a wise decision because the University was working on ion channels, which were to form an important part of Huang’s future research. These molecules are pores embedded in the cell membrane which open and close on millisecond timescales, selectively allowing ionic currents to flow in and out of the cell. The abundance of ion channels in the plasma membrane of the vascular smooth muscle cells has raised many questions about their functional role in controlling blood pressure.

Huang continued the study of ion channels at University of California, Los Angeles but no longer in the vascular cells. Instead Huang worked in a team investigating potassium channels, the most widely distributed type of ion channel which are found in virtually all living organisms and are involved in a multitude of physiological functions.

In 1993 Huang made the decision not to continue his life and work in the USA and looked for a suitable position in Mainland China, Hong Kong or Singapore, eventually accepting a lecturership at CUHK in 1993 but it was a slow start.

“At that time, I had no funding for research and only limited laboratory facilities,” he says.

Short of resources, Huang started his own laboratory and after 18 months felt comfortable enough to engage his fist lab technician, who still works with him now. Nearly 24 years later, the impressive laboratory employs a team of about 15 postgraduate and postdoctoral researchers.

The chemical nitric oxide (NO) is key among the stimulants of the endothelial cells, and a focal point of Huang’s work for the past decade. NO is an anti-inflammatory gas molecule, so its production is essential in regulating damage to the cardiovascular system. The endothelial cells, which line not only blood vessels but also the lymphatic system, emit this chemical.

In 1998-9 the Huang Laboratory investigated whether polyphenols from green or black tea, and several Chinese medicinal herbs stimulate the production of NO in endothelial cells. It was important work because NO regulates blood pressure by dilating arteries; it relaxes narrowed blood vessels, increasing oxygen and blood flow, so alleviating metabolic and vascular diseases. Impaired NO bioactivity is an important component of hypertension and diabetes, and Huang started investigating NO’s role in the regulation of vascular function and blood pressure.

From 2008, Huang undertook parallel molecular biological research to investigate how events inside a cell lead to NO production and why it is inhibited in pathological conditions (e.g. diabetes or reduced estrogen). He found that oxidative stress in endothelial cells produces excessive free radicals which are the “bad guys” and actively capture and inactivate NO. How free radicals are generated and how they impair NO at certain levels became a major focus for research which was directly relevant to the clinical treatment of cardiovascular dysfunction.

In one of the major research highlights, Huang’s team discovered the vascular benefit of vitamin D which could reduce the accumulation of harmful free radicals in the wall of arteries from hypertensive animals and patients. They provided the first line of evidence showing that chronic treatment with calcitriol, an active form of vitamin D, protects against renovascular function in hypertension. The findings in human renal arteries and human endothelial cells were confirmed both by in vitro and in vivo results in hypertensive rats. These findings support clinical observations that an inverse correlation exists between the vitamin D level in the blood and the incidence of cardiovascular mortality, and elevation of arterial blood pressure.

In 2014, the award of a Croucher Senior Research Fellowship allowed Huang to undertake a detailed investigation of the benefits of physical exercise to vascular function and the potential development of what is popularly described as the ‘exercise pill’. It was the first study of the topic ever conducted in Hong Kong. Exercise, Professor Huang showed, counteracts the effects of obesity and diabetes and causes the endothelial cells to function normally.

Last year the Huang laboratory produced a key paper, published in the journal, Nature, on how blood flow patterns can trigger vascular inflammation and atherosclerosis (the disease of the large arteries in which plaque builds up). Huang’s team demonstrated that certain endothelial cell activity is regulated by different patterns of blood flow and proved that the Hippo signaling pathway, which tells endothelial cells how to react, responds differently to varied patterns of blood flow. A straight blood vessel with normal blood flow can stimulate the endothelial cells to produce NO. But when blood vessels are curved or arched, or have narrow branches, the flow gets disturbed. This causes greater production of free radicals that induce inflammation, as well as reducing the production of beneficial NO. Uncovering how the Hippo pathway signals to other cellular events will allow for the screening of existing small-molecule drugs to see if they are effective in targeting the pathway in the treatment of atherosclerosis.

“It has been one of the most important findings of this lab “ says Huang.

Professor Yu Huang received his B.Sc. degree from Fudan University Shanghai Medical School, and M.Phil and PhD degrees from University of Cambridge. After spending several years on research in the United States, first as the American Heart Association postdoctoral research fellow in the University of Vermont and later as postdoctoral physiologist at University of California at Los Angeles, he joined the Department of Physiology, CUHK in late 1993 and is currently Professor in the School of Biomedical Sciences. He is the founding Director (Basic Sciences) of the Institute of Vascular Medicine at CUHK.

To view Professor Huang’s Croucher profile, please click here