Angiotensinogen Gene Knockout Delays and Attenuates Cold-Induced Hypertension

Abstract

Abstract-The aim of the present study was to assess our hypothesis that the renin-angiotensin system (RAS) is responsible for cold-induced hypertension and cardiac hypertrophy. Two groups of wild-type (WT) mice and 2 groups of angiotensinogen gene knockout (Agt-KO) mice (6 per group) were used. After blood pressures (BP) of the four groups were measured 3 times at room temperature (25°C), 1 WT and 1 Agt-KO group were exposed to cold (5°C). The remaining groups were kept at 25°C. BP of the cold-exposed WT group increased significantly in 1 week of cold exposure and rose gradually to 168Ϯ7 mm Hg by week 5, whereas the BP of the Agt-KO group did not increase until week 3. The cold-induced increase in BP (⌬BP) was decreased significantly in the Agt-KO mice (19Ϯ3 mm Hg) compared with that of the WT mice (61Ϯ5 mm Hg) by 5 weeks of exposure to cold. Both WT and Agt-KO groups had cardiac hypertrophy in cold to the same extent. Agt-KO caused a significant increase in nitric oxide (NO) production. Thus, the RAS may inhibit NO formation. Chronic cold exposure decreased NO production, which may be mediated partially by activation of the RAS. These results strongly support that the RAS plays a critical role in the development of cold-induced hypertension but not cardiac hypertrophy. Moreover, the role of the RAS in cold-induced hypertension may be mediated in part by its inhibition on NO production. [3][4][5]7,8 frequently that cold winter weather makes hypertension more severe in hypertensive patients and is associated with an increased incidence of stroke and myocardial infarction. Normal human subjects have seasonal variations in blood pressure, with higher pressure in winter. 9 -13 Donaldson et al, 2 after studying the relation between outdoor temperature and blood pressure in men in central London between 1986 and 1992, reported that cold exposure of normal life in winter is sufficient to induce significant and prolonged hypertension in the general population. Exposure of the bare face to cold could induce a significant elevation of systolic and diastolic blood pressure in normotensive subjects dressed in cold-protective clothing. 14 Thus, low environmental temperature is an important factor contributing to the high incidence of hypertension and the high cardiovascular mortality in cold (north) regions.Previous studies [15][16][17][18][19][20][21][22] from this laboratory have shown that chronic exposure of rats to mild cold (5°C or 41°F) induces hypertension including cardiac hypertrophy. This is presently the only "naturally occurring" form of experimentally induced hypertension that is induced without surgical intervention, administration of large doses of drugs or hormones, or genetic manipulation. Thus, it is important to understand fully the mechanism contributing to this unique model of hypertension because it is naturally occurring. It is notable that the elevated blood pressure of rats after 7 weeks of exposure to cold does not return to precold exposure level during 4 weeks after removal from cold. 23 Thus, a...

AAV delivery of mineralocorticoid receptor shRNA prevents progression of cold-induced hypertension and attenuates renal damage

“…Animals did not appear stressed during BP measurement. The tail-cuff method is a common method used by Sun et al, [27][28][29] Wang et al, 31,32 Peng et al 33 and Zhu et al 34 to delineate CIH. It has been confirmed by the intraarterial cannulation that the non-invasive tail-cuff method is effective and reliable in monitoring systolic BP in rats exposed to cold.…”

“…[15][16][17][18] Cold temperatures make hypertension more severe in hypertensive patients. 10,14,15,[19][20][21] Chronic cold exposure induces hypertension and cardiac hypertrophy in rats within 1-3 weeks, 22,27,31,32 namely CIH. Cold-induced hypertension is a natural form of experimentally induced hypertension that does not require surgery, administration of large doses of hormones or drugs, or genetic manipulation.…”

“…[22][23][24] Cold-induced hypertension model was chosen for in vivo test because CIH is associated with the overactivity of the RAAS. [25][26][27][28][29] We hypothesized that AAV delivery of MR-shRNA attenuates CIH and renal damage.…”

Overview of recent advances in molecular cardiology

“…In some cases, the development of cardiac hypertrophy is the result of compensatory responses of the heart to increased hemodynamic load. However, some forms of cardiac hypertrophy are independent of pressure overload (1,2). Endocrine factors (catecholamines, angiotensin II, thyroxine hormone, cytokines, etc) or primary genetic abnormalities can cause cardiac hypertrophy.…”

“…Perhaps a better way to determine the role of a specific gene in pressure-overload hypertrophy is to evaluate the hypertrophic response of rodents lacking or overexpressing this gene (5). One study (2) found that angiotensinogen gene knockout did not affect the development of cardiac hypertrophy in cold-exposed mice, suggesting that the reninangiotensin system is not involved in cold-induced cardiac hypertrophy, a form of hypertrophy independent of pressure overload (6). Similarly, mice lacking AT 1A receptors have been found to develop cardiac hypertrophy to the same extent as wild-type mice do in response to aortic banding or chronic cold exposure (7,8), indicating that AT 1A receptors do not play a role in these models of cardiac hypertrophy.…”