Essential hypertension is extremely prevalent in the population, and a significant percentage of these patients manifest salt-sensitive hypertension. Although the etiology of salt-sensitive hypertension is undoubtedly multifactorial, there is experimental and epidemiologic evidence linking abnormalities in the cyclooxygenase (COX)/prostaglandin system to pathogenesis. COX-2 inhibitors, as well as non-selective non- steroidal anti-inflammatory drugs (NSAIDs) are known to elevate blood pressure (BP) and antagonize the BP- lowering effect of antihypertensive medication in many users. NSAIDs and COX-2 inhibitors can also induce peripheral edema in certain patients. Selective inhibition of COX-2 has been implicated in increased cardiovascular mortality, which appears to be multifactorial, and may involve increases in BP and salt and water retention Thus, COX-2 activity seems to be an important mediator of salt and water homeostasis and a guard against development of salt-sensitive hypertension. The mechanism by which COX-2 inhibition leads to development or exacerbation of salt-sensitive hypertension has been generally thought to be due primarily to inhibition of intrinsic renal COX-2 activity, since salt loading up-regulates COX- expression in renal medulla, and COX-2 inhibitors reduce urinary sodium excretion. However, we have found that transplanting bone marrow from mice deficient in COX-2 or the major prostaglandin E2 synthase associated with COX-2 (mPGES- 1) into wild type mice leads to the development of salt-sensitive hypertension. These findings indicate that previous paradigms about the development of salt-sensitive hypertension are incomplete. More importantly, these findings suggest a completely novel and unexplored role for COX-2 generated prostaglandins from bone marrow-derived cells in regulation of blood pressure homeostasis as well as salt and water regulation. These observations suggest that COX-2 metabolites generated from bone marrow-derived cells may partner with COX-2 metabolites from intrinsic renal cells to prevent development of salt-sensitive hypertension. As a corollary, we will also test whether inhibition of COX-2 metabolites specifically from bone marrow-derived cells is a central factor in NSAID-mediated hypertension and edema. To investigate underlying mechanisms of this novel role of bone marrow-derived COX-2 in regulation of blood pressure, we have developed three specific aims:
Specific Aim #1 will determine the role of prostaglandins generated from COX-2 expression in eitherbone marrow-derived cells in regulation of salt and water homeostasis;
specific aim #2 will determine mechanism(s) by which COX-2 generated prostaglandins from bone marrow-derived bells mediate salt- sensitive hypertension.
Aim #3 will examine underlying mechanisms by which COX-2 inhibition can predispose to development of peripheral edema. In summary, these studies will test a novel and innovative hypothesis concerning the underlying mechanisms of hypertension.
The proposed studies will investigate the role of prostaglandins derived from COX-2 generated from bone marrow derived cells. The studies will investigate mechanisms by which this population of cells may respond to salt loading and the mechanisms by which either deletion of inhibition of COX-2 expression or prostaglandin signaling in these cells can induce and exacerbate salt-sensitive hypertension.
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