Abstract-To evaluate the role of thromboxane in hypertension and its complications, we studied mice with targeted disruption of the TXA2 receptor gene in an angiotensin-II-dependent model of hypertension. To determine whether genetic background might alter the physiological actions of the TP receptor, we studied two lines of TP knockout (Tp Ϫ/Ϫ ) mice with distinct genetic backgrounds (C57BL/6 and BALB/c). During chronic angiotensin II infusion (1000 ng/kg per minute ϫ 28 days by subcutaneous osmotic pump), TP deficiency prevented mortality in the C57BL/6 background but not in the BALB/c strain. Chronic angiotensin II infusion also caused a rapid and significant increase in blood pressure in wild-type (WT) C57BL/6 and BALB/c animals, which was significantly attenuated in Tp Ϫ/Ϫ mice on either background. After 28 days of infusion, cardiac hypertrophy only occurred in the C57BL/6 strain: heart/body weight ratio increased by 57%Ϯ8% in WT mice compared with 17%Ϯ6.5% for the Tp Ϫ/Ϫ mice (PϽ0.01). Chronic angiotensin II infusion caused albuminuria only in the C57BL/6 strain, and TP deficiency did not alter its development. Cyclooxygenase-1 knockout mice also had attenuated blood pressure increase during chronic angiotensin II infusion, suggesting that cyclooxygenase-1 metabolites are involved in angiotensin-II-dependent hypertension. Thus, on the C57BL/6 background, TP receptors contribute to cardiac hypertrophy but not proteinuria. However, irrespective of genetic background, the TP receptor makes a robust contribution to the pathogenesis of angiotensin II-dependent hypertension. (TxA2) is produced by the metabolism of arachidonic acid through the cyclooxygenase-1 (COX1) and cyclooxygenase-2 pathway. TxA2 is a potent vasoconstrictor and platelet aggregate. 1 In addition, TxA2 regulates renal hemodynamics and sodium handling. [2][3][4] Based on its biological actions, TxA2 has been implicated in the pathogenesis of cardiovascular diseases including ischemic heart disease, 5 atherosclerosis, 6 and eclampsia, 7 although the precise COX isoform mediating these actions is still unclear. Interactions between TxA2 and the renin-angiotensin system have also been established. For example, angiotensin II (Ang II) stimulates TxA2 synthesis in vascular and renal tissues. 8,9 Moreover, there is evidence for common actions of Ang II and TxA2 to promote systemic and renal vasoconstriction, sodium handling, 10 and vascular smooth muscle cell proliferation. 11 These interactions suggest a potential contribution of TxA2 acting through the thromboxane A2 (TP) receptor to the pathogenesis of hypertension and its complications. Here, using a genetic approach, we examine the role of TP receptors and the COX1 pathway in a model of Ang-II-dependent hypertension and its cardiac and renal complications. Methods Establishment of the TP Receptor and COX1 Knockout Mice LinesThe thromboxane A2 (TP) knockout (Tp Ϫ/Ϫ ) mice were generated as previously described. 12 The TP mutation was backcrossed onto two different inbred genetic backgrounds for...

Specific inhibitors of COX-2 have been associated with increased risk for cardiovascular complications. These agents reduce prostacyclin (PGI2) without affecting production of thromboxane (Tx) A2. While this abnormal pattern of eicosanoid generation has been implicated in the development of vascular disease associated with COX-2 inhibition, its role in the development of hypertension, the most common cardiovascular complication associated with COX-2 inhibition, is not known. We report here that mice lacking the receptor for PGI2 (IPKOs) develop salt-sensitive hypertension, cardiac hypertrophy, and severe cardiac fibrosis. Coincidental deletion of the TxA2 (TP) receptor does not prevent the development of hypertension, but cardiac hypertrophy is ameliorated and fibrosis is prevented in IPTP double knockouts (DKOs). Thus, deletion of the IP receptor removes a constraint revealing adverse cardiovascular consequences of TxA2. Our data suggest that adjuvant therapy that blocks unrestrained Tx actions might protect against end-organ damage without affecting blood pressure in patients taking COX-2 inhibitors.

The cytochrome P450 (CYP) enzymes participate in a wide range of biochemical functions, including metabolism of arachidonic acid and steroid hormones. Mouse CYP2J5 is abundant in the kidney where its products, the cis-epoxyeicosatrienoic acids (EETs), modulate sodium transport and vascular tone. To define the physiological role of CYP2J5 in the kidney, knockout mice were generated using a conventional gene targeting approach. Cyp2j5 (-/-) mice develop normally and exhibit no overt renal pathology. While renal EET biosynthesis was apparently unaffected by the absence of CYP2J5, deficiency of this CYP in female mice was associated with increased blood pressure, enhanced proximal tubular transport rates, and exaggerated afferent arteriolar responses to angiotensin II and endothelin I. Interestingly, plasma 17beta-estradiol levels were reduced in female Cyp2j5 (-/-) mice and estrogen replacement restored blood pressure and vascular responsiveness to normal levels. There was no evidence of enhanced estrogen metabolism, or altered expression or activities of steroidogenic enzymes in female Cyp2j5 (-/-) mice, but their plasma levels of luteinizing hormone and follicle stimulating hormone were inappropriately low. Together, our findings illustrate a sex-specific role for CYP2J5 in regulation of blood pressure, proximal tubular transport, and afferent arteriolar responsiveness via an estrogen-dependent mechanism.