Background and Purpose Systemic hypertension has long been considered as a risk factor of aneurysmal rupture. However, a causal link between systemic hypertension and the development of aneurysmal rupture has not been established. In this study, using a mouse model of intracranial aneurysm rupture, we examined the roles of systemic hypertension in the development of aneurysmal rupture. Methods Aneurysms were induced by a combination of deoxycorticosterone acetate (DOCA)-salt induced hypertension and a single injection of elastase into the cerebrospinal fluid in mice. Anti-hypertensive treatment was started six days after aneurysm induction. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysm with subarachnoid hemorrhage. Hydralazine (direct vasodilator) or the discontinuation of the DOCA-salt treatment was used to assess the roles of systemic hypertension. Captopril (angiotensin converting enzyme inhibitor) or losartan (angiotensin II type 1 receptor antagonist) was used to assess the roles of the local renin-angiotensin system in the vascular wall. Results Normalization of blood pressure by hydralazine significantly reduced the incidence of ruptured aneurysms and the rupture rate. There was a dose dependent relationship between the reduction of blood pressure and the prevention of aneurysmal rupture. Captopril and losartan were able to reduce the rupture rates without affecting systemic hypertension induced by DOCA-salt treatment. Conclusions Normalization of blood pressure after aneurysm formation prevented aneurysmal rupture in mice. In addition, we found that the inhibition of the local renin-angiotensin system independent from the reduction of blood pressure can prevent aneurysmal rupture.

Clinical observations suggest that post-menopausal women have a higher incidence of aneurysmal rupture than premenopausal women. We hypothesize that a relative deficiency in estrogen may increase the risks for aneurysmal growth and subarachnoid hemorrhage in post-menopausal women. We assessed the effects of estrogen and selective estrogen receptor subtype agonists on the development of aneurysmal rupture in ovariectomized female mice. We utilized an intracranial aneurysm mouse model that recapitulates the key features of human intracranial aneurysms, including spontaneous rupture. Ten- to twelve-week-old ovariectomized female mice received treatment with estrogen, non-selective estrogen receptor antagonist, estrogen receptor-α agonist, or estrogen receptor-β agonist starting 6 days after aneurysm induction so that the treatments affected the development of aneurysmal rupture without affecting aneurysmal formation. Estrogen significantly reduced the incidence of ruptured aneurysms and rupture rates in ovariectomized mice. Non-selective estrogen receptor antagonist abolished the protective effect of estrogen. Though estrogen receptor-α agonist did not affect the incidence of ruptured aneurysms or rupture rates, estrogen receptor-β agonist prevented aneurysmal rupture without affecting the formation of aneurysms. The protective role of estrogen receptor-β agonist was abolished by the inhibition of nitric oxide synthase. We showed that estrogen prevented aneurysmal rupture in ovariectomized female mice. The protective effect of estrogen appeared to occur through the activation of estrogen receptor-β, a predominant subtype of estrogen receptor in human intracranial aneurysms and cerebral arteries.

Insulin-dependent translocation of glucose transporter 4 (Glut4) to the plasma membrane plays a key role in the dynamic regulation of glucose homeostasis. We recently showed that this process is critically dependent on palmitoylation of Glut4 at Cys-223. To gain further insights into the regulation of Glut4 palmitoylation, we set out to identify the palmitoyl acyltransferase (PAT) involved. Here we report that among 23 mammalian DHHC proteins, DHHC7 is the major Glut4 PAT, based on evidence that ectopic expression of DHHC7 increased Glut4 palmitoylation, whereas DHHC7 knockdown in 3T3-L1 adipocytes and DHHC7 KO in adipose tissue and muscle decreased Glut4 palmitoylation. Moreover, inactivation of DHHC7 suppressed insulin-dependent Glut4 membrane translocation in both 3T3-L1 adipocytes and primary adipocytes. Finally, DHHC7 KO mice developed hyperglycemia and glucose intolerance, thereby confirming that DHHC7 represents the principal PAT for Glut4 and that this mechanism is essential for insulin-regulated glucose homeostasis.

Background Epidemiological studies have indicated that post-menopausal women have a higher incidence of intracranial aneurysms than men in the same age group. Objective We sought to investigate whether estrogen or estrogen receptors (ERs) mediate protective effects against the formation of intracranial aneurysms. Methods Intracranial aneurysms were induced in mice by combining a single injection of elastase into the cerebrospinal fluid with deoxycorticosterone acetate salt hypertension. The mice were treated with estrogen (17β-estradiol), ERα agonist (propylpyrazole-triol), and ERβ agonist (diarylpropionitrile) with and without a nitric oxide synthase inhibitor. Results The ovariectomized female mice had a significantly higher incidence of aneurysms than the male mice, which was consistent with past epidemiological studies. In ovariectomized female mice, an ERβ agonist, but not an ERα agonist or 17β-estradiol, significantly reduced the incidence of aneurysms. The protective effect of the ERβ agonist was absent in the ovariectomized ERβ knockout mice. The protective effect of the ERβ agonist was negated by treatment with a nitric oxide synthase inhibitor. Conclusions The effects of gender, menopause, and estrogen treatment observed in this animal study were consistent with previous epidemiological findings. Stimulation of estrogen receptor-β was protective against the formation of intracranial aneurysms in ovariectomized female mice.