Objective Obesity promotes hypertension, but it is unclear if sex differences exist in obesity-related hypertension. Angiotensin converting enzyme 2 (ACE2) converts angiotensin II (AngII) to angiotensin-(1–7) (Ang-[1–7]), controlling peptide balance. We hypothesized that tissue-specific regulation of ACE2 by high-fat (HF) feeding and sex hormones contributes to sex differences in obesity-hypertension. Methods and Results HF-fed females gained more body weight and fat mass than males. HF-fed males exhibiting reduced kidney ACE2 activity had increased plasma angiotensin II levels and decreased plasma Ang-(1–7) levels. In contrast, HF-fed females exhibiting elevated adipose ACE2 activity had increased plasma Ang-(1–7) levels. HF-fed males had elevated systolic and diastolic blood pressure that were abolished by losartan. In contrast, HF-fed females did not exhibit increased systolic blood pressure until females were administered the Ang-(1–7) receptor antagonist, D-Ala-Ang-(1–7). Deficiency of ACE2 increased systolic blood pressure in HF-fed males and females, which was abolished by losartan. Ovariectomy of HF-fed female mice reduced adipose ACE2 activity and plasma Ang-(1–7) levels, and promoted obesity-hypertension. Finally, estrogen, but not other sex hormones, increased adipocyte ACE2 mRNA abundance. Conclusions These results demonstrate that tissue-specific regulation of ACE2 by diet and sex hormones contributes to sex differences in obesity-hypertension.
Infusion of ANG II in hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). The purpose of this study was to define the contribution of ANG II-induced hypertension to these vascular pathologies. Male apolipoprotein E (apoE)- and LDL receptor (LDLr)-deficient mice were infused with ANG II (1,000 ng.kg(-1).min(-1)) or norepinephrine (NE; 5.6 mg.kg(-1).day(-1)) for 28 days. Infusion of ANG II or NE increased mean arterial pressure (MAP; ANG II, 133 +/- 2.8; NE, 129 +/- 13 mmHg) to a similar extent compared with baseline blood pressures (MAP, 107 +/- 2 mmHg). Abdominal aortic width increased in both apoE-deficient (apoE(-/-)) or LDLr-deficient (LDLr(-/-)) mice infused with ANG II (apoE(-/-): 1.4 +/- 0.1; LDLr(-/-): 1.6 +/- 0.2 mm). In contrast, NE did not change diameters of abdominal aortas (apoE(-/-): 0.91 +/- 0.03; LDLr(-/-): 0.87 +/- 0.02 mm). Similarly, atherosclerotic lesions in aortic arches were much greater in mice infused with ANG II compared with NE. At a subpressor infusion rate of ANG II (500 ng.kg(-1).min(-1)), AAAs developed in 50% of apoE(-/-) mice. Alternatively, administration of hydralazine (250 mg/l) to ANG II-infused apoE(-/-) mice (1,000 ng.kg(-1).min(-1)) lowered systolic blood pressure (day 28: ANG II, 157 +/- 6; ANG II/hydralazine, 135 +/- 6 mmHg) but did not prevent AAA formation or atherosclerosis. These results demonstrate that infusion of ANG II to hyperlipidemic mice induces AAAs and augments atherosclerosis independent of increased blood pressure.
Background Genome-wide association studies (GWAS) have established ADAMTS7 as a locus for coronary artery disease (CAD) in humans. Yet, these studies fail to provide directionality for the association between ADAMTS7 and CAD. Previous reports have implicated ADAMTS7 in the regulation of vascular smooth muscle cell (VSMC) migration, but a role and direction of impact for this gene in atherogenesis has not been shown in relevant model systems. Methods and Results We bred an Adamts7 whole body knockout (KO) mouse onto both the Ldlr and Apoe KO hyperlipidemic mouse models. Adamts7−/−/Ldlr−/− and Adamts7−/−/Apoe−/− mice displayed significant reductions in lesion formation in aortas and aortic roots as compared to controls. Adamts7 KO mice also showed reduced neointimal formation after femoral wire injury. Adamts7 expression was induced in response to injury and hyperlipidemia but was absent at later timepoints, and primary Adamts7 KO VSMCs showed reduced migration in the setting of TNFα stimulation. ADAMTS7 localized to cells positive for SMC markers in human CAD lesions, and sub-cellular localization studies in cultured VSMCs placed ADAMTS7 at the cytoplasm and cell membrane, where it co-localized with markers of podosomes. Conclusions These data represent the first in vivo experimental validation of the association of Adamts7 with atherogenesis, likely through modulation of vascular cell migration and matrix in atherosclerotic lesions. These results demonstrate that Adamts7 is proatherogenic, lending directionality to the original genetic association and supporting the concept that pharmacological inhibition of ADAMTS7 should be atheroprotective in humans, making it an attractive target for novel therapeutic interventions.
Objective-Castration of male apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice reduces angiotensin II (Ang II)-induced abdominal aorta aneurysms (AAAs) to that of female mice. The purpose of this study was to determine whether this reduction is attributable to androgen-mediated regulation of aortic Ang II type 1A receptors (AT1aR). Methods and Results-AT1aR mRNA abundance in the AAA-prone region of abdominal aortas was 8-fold greater compared to thoracic aortas of male but not female mice. AT1aR mRNA abundance decreased after castration in abdominal but not thoracic aortas of male mice. Dihydrotestosterone (DHT, 0.16 mg/d) administration to castrated male mice restored AT1aR mRNA abundance in abdominal aortas but had no effect in thoracic aortas. DHT also increased AT1aR mRNA abundance in abdominal aortas from female mice. Castrated male or female apoE Ϫ/Ϫ mice were administered DHT during infusion of saline or Ang II (1000 ng/kg/min for 28 days). DHT administration did not alter serum cholesterol concentrations, lipoprotein distributions, or atherosclerotic lesion areas in either male or female mice. However, administration of DHT increased AAA incidence in male (27% placebo versus 75% DHT) and female mice (28% placebo versus 64% DHT). Key Words: angiotensin Ⅲ aneurysms Ⅲ androgen Ⅲ atherosclerosis Ⅲ sex hormones A bdominal aortic aneurysms (AAAs) account for 2% of all deaths and are the tenth most common cause of mortality. 1 The incidence and severity of abdominal aortic dilations are greater in males than females. 2,3 Male gender has been consistently identified as a nonmodifiable risk factor for AAA. However, the role of androgens as mediators of gender differences in AAA has not been investigated extensively. Conclusions-AndrogenGender differences also impact AAA formation in experimental models of this disease. In aortic dilation promoted by transient intraluminal elastase infusion, male rats had larger and more frequent AAAs than females. 4 Chronic infusion of angiotensin II (Ang II) into hyperlipidemic mice resulted in AAA formation at a higher incidence in male compared to female mice. [5][6][7][8] In agreement with a potential protection of female gender, estradiol administration to male apolipoprotein E (apoE)-deficient mice reduced Ang II-induced AAA formation. 9 However, ovariectomy of apoE Ϫ/Ϫ mice did not significantly influence AAA formation, suggesting that endogenous ovarian hormones are not primary mediators of gender differences in Ang II-induced AAAs. 8 In contrast, removal of male sex hormones by orchiectomy of apoE Ϫ/Ϫ mice significantly reduced the incidence of Ang II-induced AAAs to that observed in female mice. 8 These data potentially implicate androgen as a primary mediator of gender differences in Ang II-induced AAAs; however, mechanisms of androgen to promote AAA formation are unknown.Androgen has been reported to increase the expression of each component of the renin-angiotensin system (RAS), including angiotensinogen, renin, ACE, and AT1 receptors. 10 Previous studies in our laboratory...
Objective The renin-angiotensin system (RAS) contributes to atherosclerotic lesion formation. Angiotensin converting enzyme 2 (ACE2) catabolizes angiotensin II (AngII) to angiotensin-(1–7) (Ang-(1–7)) to limit effects of the RAS. The purpose of this study was to define the role of ACE2 in atherosclerosis. Methods & Results Male Ace2−/y mice in an LDL receptor deficient (Ldlr)−/− background were fed a high-fat (HF) diet for 3 months. ACE2 deficiency increased atherosclerotic area (Ace2+/y, 17 ± 1; Ace2−/y, 23 ± 2 mm2, P<0.002). This increase was blunted by losartan. To determine if leukocytic ACE2 influenced atherosclerosis, irradiated Ldlr−/− male mice were repopulated with bone marrow-derived cells from Ace2+/y or −/y mice and fed a HF diet for 3 months. ACE2 deficiency in bone marrow-derived cells increased atherosclerotic area (Ace2+/y, 1.6 ± 0.3; Ace2−/y, 2.8 ± 0.3 mm2; P<0.05). Macrophages from Ace2−/y mice exhibited increased AngII secretion and elevated expression of inflammatory cytokines. Conditioned media from MPMs of Ace2−/y mice increased monocyte adhesion to endothelial cells (HUVECs). Incubation of HUVECs with AngII promoted monocyte adhesion, which was blocked by Ang-(1–7). Co-infusion of Ang-(1–7) with AngII reduced atherosclerosis. Conclusions These results demonstrate that ACE2 deficiency in bone marrow-derived cells promotes atherosclerosis through regulation of AngII/Ang-(1–7) peptides.
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