Cardiac hypertrophy, or hypertrophic cardiomyopathy (HCM), is a thickening of cardiac muscle often caused by chronic high blood pressure that can lead to heart failure. Although HCM is a leading cause of sudden cardiac death in young athletes, it is a significant cause of sudden unexpected cardiac death in any age group.
A previous study showed that a heart attack or high blood pressure frequently leads to pathological heart growth and subsequently to heart failure. In that study, researchers at the Hannover Medical School and the Göttingen Max Planck Institute for Biophysical Chemistry discovered that two tiny RNA molecules played a key role in this detrimental development in mice.
When they inhibited one of those two specific molecules, they were able to protect the rodent against pathological heart growth and failure. With their findings, the scientists hoped that future studies would lead to the development of therapeutic approaches that could protect humans against heart failure.
In a new study, Mahesh Gupta, Ph.D., senior author and director of the Cardiac Cell Biology Research Program at the University of Chicago, and researchers have also been working toward protecting the human heart. In the April 2015 issue of the International Journal of Oncology, the researchers detail how they found that a natural compound from magnolia bark called honokiol — an ancient remedy widely used in Asia — can protect the heart from hypertrophy by activating SIRT3, a protein associated with delayed aging, stress resistance and metabolic regulation.
When injected into mice, honokiol (hoh-NOH-kee-ohl) reduced the excess growth of individual cardiac muscle cells, decreased ventricular wall thickness and prevented the accumulation of interstitial fibrosis, a stiffening of cardiac muscle cells that reduces their ability to contract. Honokiol also protected heart muscle cells from the damage caused by oxidative stress, which can damage DNA.
By increasing SIRT3 levels, honokiol effectively blocked both the induction and progression of cardiac hypertrophy in mice and even mitigated pre-existing cardiac hypertrophy. One of a family of sirtuin proteins, SIRT3 is primarily active in the mitochondria, the cell's main source of energy. It plays a central role there in energy metabolism and in preventing acetylation, a process that can alter the function of proteins.
In the absence of SIRT3, mitochondrial proteins become hyperacetylated, which can impair function. Human studies show that sedentary patients over 60 years old have nearly 40 percent less SIRT3. Mice that lack the gene for SIRT3 have 40 percent lower levels of ATP, a primary source of energy, than those with the gene.
In this study, the researchers tested multiple compounds in search of one that could activate SIRT3. They found that honokiol reduced mitochondrial protein acetylation. When they tested it in the heart muscle cells from mice, they found that a small amount of honokiol nearly doubled SIRT3 levels within 24 hours.
This study may be the first to describe a pharmacologic activator of SIRT3. Usually, caloric restriction combined with endurance exercise has been the only way to boost SIRT3 levels — a rigorous regimen that is difficult for many people to maintain.
Hopefully, the results of this study may potentially play a significant role in the prevention and treatment of heart failure.
