Experts Iron Out Heart Disease Wrinkles: Collagen-Producing Cream Shows Promise in Healing Damaged T

May 27, 02:03 PM

Current Headlines: By Jenni Laidman, The Blade, Toledo, Ohio

May 27--They were looking for the secrets of heart failure, for the misbehaviors inside the cells that lead to the flabby, inefficient thing that is a heart in congestive distress.

What they found? A way to reduce wrinkles and improve wound healing.

That's the beauty of basic science, Dr. Joseph Shapiro says. When the goal is simply to know, anything may be uncovered.

"It's hard to know where certain things are going to take you. We don't really know where the next breakthroughs are coming. We just like to think we do," Dr. Shapiro said.

Zijian Xie, 46, (pronounced Shay) and Dr. Shapiro, 52, researchers at the University of Toledo medical school, the former Medical College of Ohio, have long focused on heart failure.

Dr. Shapiro's interest arose from his work as a kidney specialist. He knew that 20 percent of all dialysis patients die every year, and that half of those deaths are from congestive heart failure. Clearly something was going on in end-stage kidney disease that made these patients extraordinarily vulnerable to cardiac distress. But what was it?

Dr. Xie, a molecular biologist, is a basic scientist. He approached heart failure by looking at the behavior of a tiny doorway found in cell surfaces -- a pump, actually, that controls the levels of calcium in the cell, and thereby controls the strength of each heart beat.

It has been his focus since he was a doctoral student in the lab of UT's Dr. Amir Askari, who has spent a career dissecting this cell portal's behavior.

This is the doorway that the pair opened to create wrinkle cream.

But don't go looking for a UT anti-aging elixir in stores anytime soon. A patent application awaits approval, and far more testing remains.

So far, the drug -- a variety of heart medicine -- has been tested in laboratory cell cultures and mixed with olive oil for testing in rats for its wound-healing abilities.

The drug induces some cells to make collagen, the major structural protein in the skin. To test its effects, the researchers grew a variety of cells -- including human skin cells -- and injured them, dragging a pipette across the cell surface to create a wound.

Then they compared healing rates between treated cells and untreated cells. Treated cells healed 20 to 30 percent faster than untreated cells.

They followed this test with a test on live rats, seeing how long it would take rat wounds to heal. Again, the drug-treated wounds healed 20 to 30 percent faster.

"And that's without really working on optimizing anything," Dr. Shapiro said.

"We haven't looked at concentrations. We haven't tried other additives."

Testing the medication on wrinkled skin will await the next round of development -- so no volunteers, please. The researchers will have to develop animal models for wrinkles -- something neither researchers' academic laboratories possesses.

While this ointment may prove to be a profitable finding if a company steps forward to license the technology, it may ultimately look a bit trivial beside another, more subtle discovery to come from this same work.

In fact, Dr. Xie's study of the pump overturns what everyone believed -- and some still believe -- about the pump's function.

Dr. Xie found that the pump is more than a pump. It has a second, completely distinct role in the cell. It is a commander. It can issue instructions to the rest of the cell, and get all kinds of processes moving.

Dr. Thomas Pressley of Texas Tech University Health Sciences Center in Lubbock, also an expert on this cellular pump, has gradually come to believe that Dr. Xie's conclusions are right.

"The thing that's been exciting and controversial about [Drs. Xie and Shapiro's] work is that they're breaking the paradigm," Dr. Pressley said.

"This really represents a new way of looking at an old thing. We thought we knew what was going on for the most part. Yes, we had details we needed to flesh out, but they are proposing something unexpected."

As Dr. Xie looked at how the pump also sends signals, he realized that this meant a class of drugs given to heart failure patients for nearly 200 years -- digitalis and drugs like it -- probably didn't work the way everyone thought.

"When we started to look at the therapeutic effect of digitalis on cardiac cells, we realized the concentration [of digitalis] we used was too low," Dr. Xie said. There wasn't enough digitalis to affect pumping.

Dr. Xie discovered that drugs like digitalis actually turn on the pump's command capabilities.

Drs. Shapiro and Xie conducted a series of four experiments to look at how digitalislike substances affect the rat heart.

In one experiment, they gave healthy rats low doses of a digitalislike drug. Those rats developed fibrous hearts, which worked inefficiently. They were in heart failure.

In another experiment, they gave heathy rats an antibody to block digitalislike drugs, then they injected a digitalislike drug into the rat. The antibody proved protective. Those rat hearts had far less fiber.

In a third experiment, they induced kidney disease in rats. These rats developed hearts riven with fibrous tissue, incapable of relaxing completely, and therefore inefficient at refilling.

Finally, they gave the rats with experimentally induced kidney disease an antibody to block digitalislike substances. Those rats had far less fibrous tissue.

"That study was an eye-opener," Dr. Shapiro said. "It was a smoking gun implicating [digitalislike drugs] in fibrosis."

Before anyone throws out their prescription for digitalis, it should be noted that rat hearts are more prone to fibrosis, a lot more than human hearts, Dr. Shapiro said. He said there is not enough information to determine whether digitalislike drugs have a similar effect on human hearts.

In any event, fewer doctors are prescribing these drugs. Large studies conducted in the 1990s showed that while people who take digitalis have improved heart function, they live no longer than people who do not take digitalis.

But the discovery of digitalis-induced fibrosis in rat hearts prompted the researchers to look a little further at how the fibrous tissue grew. They put a digitalislike drug into a dish of cells that specialize in collagen production in the heart -- cardiac fibroblasts. It is collagen that turns into nasty heart fiber.

The result: Increased collagen production.

"Then, to get an idea of how widespread this effect was, we tried fibroblasts from other sources, other species," Dr. Shapiro said.

Human skin fibroblasts were readily available. They added the digitalislike drug and watched what happened.

"It was like crack cocaine for this stuff, these skin fibroblasts," Dr. Shapiro said. "There were very, very dramatic increases in collagen production."

Thus, the wrinkle cream was born.

The researchers anticipate creating a spin-off company to further develop the work.

"I just don't know we're going to find a taker for this product until we commercialize it ourselves," Dr. Shapiro said.

But the wrinkle/wound-healing compound may be just the beginning.

"The pathway we have identified, this is really the novel thing," Dr. Xie said.

"Yes, digitalis for heart failure may not be good medicine, but if we can use this as a model, we may eventually think of a better version of digitalis to protect the heart."

Contact Jenni Laidman at: jenni@theblade.com or 419-724-6507.

-----

Copyright (c) 2007, The Blade, Toledo, Ohio

Distributed by McClatchy-Tribune Information Services.

For reprints, email tmsreprints@permissionsgroup.com, call 800-374-7985 or 847-635-6550, send a fax to 847-635-6968, or write to The Permissions Group Inc., 1247 Milwaukee Ave., Suite 303, Glenview, IL 60025, USA.