The results indicate that the normal role for the type of prostaglandin studied, PGF2á, is to increase blood pressure and accelerate atherosclerosis, at least in rodents, and suggest that targeting this pathway could represent a novel therapeutic approach to cardiovascular disease.
The results appeared this week in the Proceedings of the National Academy of Sciences.
“Blocking this prostaglandin receptor may provide a strategy for controlling blood pressure and its attendant vascular disease,” notes senior author Garret A. FitzGerald, MD, Director of the Institute for Translational Medicine and Therapeutics at Penn.
To address prostaglandins’ role in maintaining blood pressure, FitzGerald and his team, including researchers from the University of Southern Denmark, created strains of mice in which both the maternal and paternal copies of the gene for the PGF2á receptor were deleted. They did this in mice with a normal genetic background and in ones that contained an additional mutation in the low-density lipoprotein receptor gene. These manipulations effectively rendered the mice unable to respond to the prostaglandins.
The delicate balance the body maintains to keep blood pressure stable involves not only the prostaglandin system, but another biological pathway, the renin-angiotensin-aldosterone system, or RAAS. Under conditions of low blood pressure, the liver secretes a protein called angiotensiogen. Renin, an enzyme produced by the kidneys, cleaves angiotensiogen into a peptide called angiotensin I. Angiotensin I is cleaved again to form angiotensin II, which stimulates blood vessels to narrow, thereby increasing blood pressure. At the same time, angiotensin II induces the release of the hormone aldosterone, which further elevates blood pressure by promoting retention of water and sodium in the kidneys.
Many conventional therapies for high blood pressure target components of the RAAS pathway. For instance, ACE inhibitors such as captopril (Capoten) target the formation of angiotensin II, while aliskiren (Tekturna) targets renin.
The team assessed the impact of the PGF2á receptor mutations on both blood pressure and RAAS activity. They found that under a variety of circumstances deletion of the PGF2á receptor lowered blood pressure coincident with suppression of RAAS activity.
“Precisely how these two observations are connected is the focus of our current research,” says FitzGerald.
Blood pressure was reduced in both types of genetically engineered mice relative to control littermates. The RAAS molecules renin, angiotensin I, and aldosterone were also reduced, a biological situation leading to lower blood pressure.
The team found that the PGF2á receptor is expressed in the smooth muscle surrounding arteries in the kidneys. However, it was absent in the muscle surrounding the aorta, in the atherosclerotic lesions of mice with their PGF2á receptors knocked out, as well as in the macrophages that inhabit those lesions. Importantly, these atherosclerotic lesions were smaller and less abundant in mice that had both the low-density lipoprotein and PGF2á receptors knocked out, as was macrophage infiltration and inflammatory cytokine production, both of which are indicators of the inflammatory response that marks these plaques.
Prostaglandins are produced during the oxidation of certain cell molecules by cyclooxygenases, the COX enzymes targeted by COX inhibitors, but how remains unclear. FitzGerald’s group had previously shown that blockading cyclooxygenase 1 and its major prostaglandin product, thromboxane, also lowers blood pressure, slowing atherosclerosis, but in this previous study, the relevant genes are present in the aorta and its atherosclerotic lesions. PGF2á, by contrast, acts via the kidney and represents a distinct therapeutic opportunity.
“The picture is emerging that PGF2á controls blood pressure by a mechanism unique among the prostaglandins,” says FitzGerald. “Besides the case of thromboxane, two other types of prostaglandins, PGI2 and PGE2, stimulate renin secretion, which is part of the RAAS pathway.”
Assuming these findings can be translated to humans, targeting the PGF2á pathway could represent a novel opportunity for therapeutic control of blood pressure in cardiovascular patients.
The research was funded by the National Heart, Lung, and Blood Institute and the American Heart Association.
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Penn's School of Medicine is currently ranked #3 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to the National Institutes of Health, received over $366 million in NIH grants (excluding contracts) in the 2008 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
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Karen Kreeger | EurekAlert!
Further reports about: > COX enzymes > Cox > Heart > PGF2á > Prostaglandin > RAAS > Tekturna > UPHS > aldosterone > angiotensin II > atherosclerosis > blood flow > blood pressure > blood vessel > cardiovascular system > inflammatory cytokine production > low-density lipoprotein > macrophages > renin-angiotensin-aldosterone system > vascular disease
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