Chinese scientists have discovered a gene that may play a central and crucial role in controlling and inhibiting the onset of a variety of heart diseases and cancer.

The recently released September edition issue of Nature Cell magazine reports that a gene, called HSG, has been found to inhibit the proliferation of the vascular smooth muscle cells, or VSMCs.

This is seen by medical scientists to be the main cause of which heart diseases including atherosclerosis, a chronic disease in which loss of elasticity of the arterial walls results in impaired blood circulation, and restenosis -- the narrowing of blood vessels after surgery.

These diseases are both caused by vascular proliferative disorders, which sees abnormal increase of certain cells, such as VSMCs, in the heart, causing enlargement of tissues.

The research team, led by Kuang-Hueih Chen from the Institute of Cardiovascular Science & the Institute of Molecular Medicine from Peking University, found the number of HSG genes was markedly low in the arteries of rats suffering from heart trouble.

In contrast, when the HSG count increases in the rat's artery, the VSMC count becomes less, thus proving the gene's role as a cell proliferation suppressor.

"We have demonstrated for the first time, that rHSG (rat HSG) profoundly inhibits VSMC proliferation," Chen is quoted in the magazine article, adding the discovery reveals an important therapeutic target for the treatment of vascular proliferative disorders and possibly other hyper-proliferative diseases.

Kenneth Chien and Masahiko Hoshijima, two US-based researchers from the University of California in San Diego, rated the study as an "important contribution to one of the forefront area of medicine research" in their review, which was published together with Chen's article.

They said the study revealed HSG plays a new role as a novel checkpoint in the pathway for the VSMC proliferation.

"The findings may have important implications for other cell types in diverse model systems," they said.

They also noted these studies may "have potentially important clinical implications" as the proliferation of vascular smooth muscle cells (VSMCs) is critical in heart diseases which causes blocked arteries by thickening cholesterol and lipids on the innermost layer of the walls of large and medium-sized arteries, or the narrowing arteries that resulted from certain heart surgeries.

The increase of VSMC and migration into the interior of the artery are key mechanisms that narrow the coronary artery, they said.

Looking for new genes that can block such a process and spell out their mechanism, therefore, has been the quest of Chen and her colleagues for 10 years.

Ras gene search

Cell hyper-proliferation has long been considered as an important factor of cardiovascular diseases and cancer, says Chen.

In particular, she notes, vascular proliferative disorders are the most common causes of severe cardiovascular diseases, the current leading cause of death in China and the United States -- and the predicted number one killer worldwide by 2020.

Coronary artery disease is already the single largest cause of death resulting from illness in the world, accounting for over one fourth of the total.

VSMCs, which are located primarily in the artery, have been found to be the major source of such proliferation. They are normally non-proliferative, but injury or mechanical stress of arteries, which may result from heart surgery, can cause the VSMCs to migrate and proliferate, resulting in expansion of the artery.

"This VSMC proliferation constitutes a primary cause factor in vascular proliferative disorders," said Chen.

The VSMCs cell proliferation is controlled by certain stimuli that are involved in the regulation of cell growth and division.

These stimuli share a final common pathway, known as the cell cycle, through which they send the signals of proliferation to activate the VSMCs.

Chen and her colleagues found the HSGs work by inhibiting a major component of the pathway, a gene family known as Ras, thus blocking the sending of the signal of proliferation to the VSMCs. "Without orders passed to them, the vascular smooth muscle cells will not proliferate, and thus will prevent the onset of the disease," said Tang Jian, another researcher on Chen's team.

The Ras is a group of cancer-causing genes that are essential for cells to be activated to pass through the cycle.

For the past 30 years, the Ras gene family has been extensively studied for its role in initiating tumors. But over the past decade, a growing body of evidence began to emerge that Ras has also been at the centre of the pathways for a diverse of cardiovascular diseases, including heart enlargement and failure.

Searching for inhibitors of Ras genes has been the goal of researchers who both work on cancers and cardiovascular diseases.

Chen and her colleagues discovered the new, inhibitory role of HSG, which is known to have important roles in the fusion of mitochondria, the power centers of the cell that provides the energy it needs to move, divide, and produce secretory products.

They compared the inbred strains of hypertensive and normal rats. The hypertensive rats had accelerated vascular proliferative disease, which is reflected by a markedly increased rate of proliferation of VSMCs compared with normal cells.

Chen found the HSG is markedly low in hypertensive rats, while over expression of HSG markedly inhibited the Ras-initiated VSMC proliferation.

Moreover, their studies have also shown that HSGs also have a potent anti-proliferative effect in a variety of cancer cells, particularly in breast cancer.

A number of therapeutic approaches have been designed by researchers to inhibit VSMC proliferation on the basis of interrupting the signal-sending pathways that result in entry of the cells into the cell cycle.

Several forms of therapies have been tested in clinical trials, all with varying effects.

"The current study by Chen and her colleagues suggests another novel approach to inhibit Ras and the VSMC cell cycle through regulation of HSG," Chien noted in the review.

Tang also noted the new discovery may open the door to a new research area and prompt researchers to re-think the role of Ras and their work on the gene family over the past 30 years.

"It can be expected that more international efforts will soon follow," he said.

(China Daily September 15, 2004)