Hearts and HIFs
Does the cellular hypoxia response contribute to heart disease? The idea is somewhat radical, since the response has been thought to protect heart cells when their blood supply is limited by disease-constricted arteries. But HHMI investigator William Kaelin has been turning up strong evidence that it can be harmful. In a paper published September 2010 in Circulation, he and his Harvard Medical School colleagues reported classic signs of heart disease in mice when their levels of HIF1α a key part of a protein complex that switches on most of the hypoxia response in cells—are kept high for long periods.
“HIF1α appears to be something of a double-edged sword,” Kaelin says. “During a heart attack, in which there’s an acute interruption of blood flow to the heart muscle, it is probably beneficial. But we now suspect that if a reduction in blood flow is sustained over weeks or months, and HIF1α levels stay high, the continuous hypoxia response can become detrimental, so that eventually the heart fails.”
Kaelin is best known in the oxygen-signaling field for his illumination of the complex process by which HIF1α levels are normally kept low. In 2001, for example, he and his colleagues reported in Science that when oxygen levels are normal, oxygen-containing hydroxyl molecules are linked to HIFα proteins in a way that leads to their swift destruction by cellular waste-disposal mechanisms. This hydroxyl modification requires the help of enzymes known as prolyl hydroxylases.
At the time, Kaelin and others in the field believed that a reduced oxygen level from plaque-constricted coronary arteries was the chief cause of progressive heart disease. Kaelin’s group looked for a way to keep the HIFα response switched on to improve heart cells’ ability to withstand this reduced oxygen level. The prolyl hydroxylase enzymes offered a straightforward approach: blocking the enzymes with drugs would allow HIF1α levels to rise, thus turning on the hypoxia response.
But as the research progressed, Kaelin and his colleagues found something unexpected. They developed transgenic mice whose primary HIF-regulating prolyl hydroxylase could be inactivated—mimicking the effect of an enzyme-inhibiting drug—and found that over time they fared worse than control mice. Although their HIF1α levels and other markers of the hypoxia response increased as planned, their hearts became diseased, and the mice died young. Kaelin wondered if a chronic hypoxia response might be part of the problem in heart disease rather than a solution.
The next step for Kaelin and his team is to determine the molecular details of how the hypoxia response leads to the damage seen in heart cells. In early follow-up research, they’ve already observed that it upregulates a general waste-disposal process within cells known as autophagy. Increased autophagy appears to contribute to a die-off of mitochondria, the tiny oxygen reactors that produce energy in cells. Without enough mitochondria, cells decline and die.
“We have some preliminary evidence to suggest that by blocking autophagy, we might actually blunt these deleterious effects of chronic HIF1α activation,” says Kaelin.
-- Jim Schnabel
HHMI Bulletin, May 2011