Grant: Project Grant

Approximately 17.7 million deaths worldwide were attributed to diseases of the cardiovascular system by the World Health Organization. About 80% are due to heart attack or stroke. It is predicted that by 2030, almost 23.6 million people will die from heart disease and stroke. Furthermore, these problems are increasing in prevalence in both women and the developing world, making cardiovascular health an increasing significant target to improve the health and well-being of society. In the late 1990s, a small protein hormone, named apelin, was discovered in the human body which has a wide variety of physiological functions; including regulation of blood pressure. Apelin has been shown to have potent vasodilator activity, which effectively widens blood vessels and lowers blood pressure. More critical for our study, recent work on apelin has shown that it plays a significant role in the recovery of damaged heart and arterial tissues after heart attacks, leading to improved chances of survival in mouse models. Despite all these beneficial cardiovascular effects, this molecule only has a short lifespan of a few minutes in the bloodstream before other proteins in the blood cut it into smaller fragments. These apelin fragments have limited effects on the regulation of blood pressure and also the recovery of heart tissue from trauma. We propose to use chemical synthesis to make analogues of apelin that retain similar shape (conformation) of this natural hormone, while altering the specific sites that are cut by proteins in the bloodstream. The slight variations in structure introduced will allow the apelin analogs to become more resistant to being cut, thereby prolonging the beneficial physiological effects. This will provide stable long-lasting drug candidates for further development and testing as therapeutic agents. We also propose to make them orally active. Such drugs may be useful for other problems, including loss of muscle mass due to aging (sarcopenia).