Role for Thromboxane Receptors in Angiotensin-II–Induced Hypertension

Abstract

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...

Asociación y efectos de interacción en los genes AGT, AGTR1, ACE, ADRB2, DRD1, ADD1, ADD2, ATP2B1, TBXA2R y PTGS2 sobre la hipertensión en población antioqueña

“…Los principales sistemas fisiológicos que se encuentran involucrados en el control de la presión arterial son el sistema renina-angiotensina-aldosterona, el endotelio vascular, la transducción de señales por vía del sistema nervioso y las proteínas del citoesqueleto, que se encargan del mantenimiento del flujo sanguíneo (presión sanguínea y volumen de fluidos extracelulares en el cuerpo), mediación de reacciones de vasodilatación-vasoconstricción y la regulación de la concentración de sales (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44).…”

Thromboxane Receptors in Smooth Muscle Promote Hypertension, Vascular Remodeling, and Sudden Death

“…Although many prostanoid metabolites are vasodilatory, TxA 2 stimulation of smooth muscle cells leads to potent vasoconstriction. TxA 2 has been implicated to be detrimental in the pathogenesis of a variety of cardiovascular diseases, including ischemic heart disease, 1 atherosclerosis, 2 hypertension, 3 preeclampsia, 4 and stroke. 5 Its actions are mediated by the thromboxane-prostanoid (TP) receptor, a member of the 7-transmembrane, G protein-coupled receptor superfamily.…”

“…13 On the other hand, several studies suggest that TP receptors make significant contributions to the pathogenesis of hypertension, especially hypertension associated with activation of the renin-angiotensin system. 3,14,15 During angiotensin II (Ang II)-induced hypertension, urinary levels of the renal TxA 2 metabolite thromboxane B 2 (TxB 2 ) increase significantly. 14,16 Thromboxane antagonists attenuate the development of hypertension associated with chronic infusion of Ang II 3 and obesity.…”

“…3,14,15 During angiotensin II (Ang II)-induced hypertension, urinary levels of the renal TxA 2 metabolite thromboxane B 2 (TxB 2 ) increase significantly. 14,16 Thromboxane antagonists attenuate the development of hypertension associated with chronic infusion of Ang II 3 and obesity. 17 Similarly, TP receptor-deficient mice are resistant to the development of Ang II-dependent hypertension and have an attenuated increase in blood pressure with N G -nitro-larginine methyl ester administration.…”

“…17 Similarly, TP receptor-deficient mice are resistant to the development of Ang II-dependent hypertension and have an attenuated increase in blood pressure with N G -nitro-larginine methyl ester administration. 3,14,18 TP receptors are expressed in a number of cell lineages with the potential to influence blood pressure, including VSMCs, 19 renal epithelium, 9 inflammatory cells, and the central nervous system. 20 However, it has been difficult to determine the precise cell lineages contributing to the ability of TP receptors to promote hypertension.…”