Involvement of Angiotensin II Type 1 Receptor and Calcium Channel in Vascular Remodeling and Endothelial Dysfunction in Rats with Pressure Overload

Abstract Aims Heart failure (HF) ensuing myocardial infarction (MI) is characterized by the initiation of a systemic inflammatory response. We aimed to elucidate the impact of myelomonocytic cells and their activation by angiotensin II on vascular endothelial function in a mouse model of HF after MI. Methods and results HF was induced in male C57BL/6J mice by permanent ligation of the left anterior descending coronary artery. Compared to sham, HF mice had significantly impaired endothelial function accompanied by enhanced mobilization of Sca-1+c-Kit+ haematopoietic stem cells and Sca-1−c-Kit+ common myeloid and granulocyte-macrophage progenitors in the bone marrow as well as increased vascular infiltration of CD11b+Ly6G−Ly6Chigh monocytes and accumulation of CD11b+ F4/80+ macrophages, assessed by flow cytometry. Using mice with Cre-inducible expression of diphtheria toxin receptor in myeloid cells, we selectively depleted lysozyme M+ myelomonocytic cells for 10 days starting 28 days after MI. While the cardiac phenotype remained unaltered until 38 days post-MI, myeloid cell depletion attenuated vascular accumulation of Nox2+CD45+ cells, endothelial dysfunction, oxidative stress, and vascular expression of adhesion molecules and angiotensin II receptor type 1 (AT1R). Pharmacological blockade of this receptor for 4 weeks did not significantly alter cardiac function, but mimicked the effects of myeloid cell depletion: telmisartan (20 mg/kg/day, fed to C57BL/6J mice) diminished bone marrow myelopoesis and myeloid reactive oxygen species production, attenuated endothelial leucocyte rolling and vascular accumulation of CD11b+Ly6G−Ly6Chigh monocytes and macrophages, resulting in improved vascular function with less abundance of Nox2+CD45+ cells. Conclusion Endothelial dysfunction in HF ensuing MI is mediated by inflammatory Nox2+ myeloid cells infiltrating the vessel wall that can be targeted by AT1R blockade.

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Calcium channel; angiotensin II type 1 receptor (AT1 receptor); angiotensin-converting enzyme (ACE); adrenergic receptor β2

Science-Business eXchange ◽

10.1038/scibx.2008.123 ◽

2008 ◽

Vol 1 (5) ◽

pp. 123-123

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Calcium Channel ◽

Adrenergic Receptor ◽

At1 Receptor ◽

Converting Enzyme

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Combined Therapy With a Calcium Channel Blocker and an Angiotensin II Type 1 Receptor Blocker

Journal of Clinical Hypertension ◽

10.1111/j.1524-6175.2007.08029.x ◽

2008 ◽

Vol 10 (s1) ◽

pp. 27-32 ◽

Cited By ~ 27

Author(s):

George L. Bakris

Keyword(s):

Angiotensin Ii ◽

Calcium Channel ◽

Calcium Channel Blocker ◽

Channel Blocker ◽

Combined Therapy ◽

Receptor Blocker

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β-Arrestin–Mediated Angiotensin II Type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension

JACC Basic to Translational Science ◽

10.1016/j.jacbts.2021.09.006 ◽

2021 ◽

Vol 6 (11) ◽

pp. 854-869

Author(s):

Zhiyuan Ma ◽

Gayathri Viswanathan ◽

Mason Sellig ◽

Chanpreet Jassal ◽

Issac Choi ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Angiotensin Ii ◽

Vascular Remodeling ◽

Receptor Activation ◽

Pulmonary Vascular Remodeling

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The angiotensin II type 1 receptor blocker azilsartan can overwhelm the sympathetic nerve activation stimulated by coadministration of calcium channel blockers

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320319839525 ◽

2019 ◽

Vol 20 (1) ◽

pp. 147032031983952 ◽

Cited By ~ 1

Author(s):

Michio Fukuda ◽

Yukako Isobe-Sasaki ◽

Ryo Sato ◽

Toshiyuki Miura ◽

Masashi Mizuno ◽

...

Keyword(s):

Angiotensin Ii ◽

Calcium Channel ◽

Calcium Channel Blockers ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

The Other ◽

Channel Blockers ◽

Nerve Activity ◽

The Relationship

Objective: In our recent study, non-Gaussianity of heart rate variability (λ25s), an indicator of sympathetic nerve activity, did not change during two-day treatment with the angiotensin II type 1 receptor blocker (ARB) azilsartan. Coadministration of calcium channel blockers (CCBs) might affect the study results. Methods: In this subanalysis, 20 patients with chronic kidney disease (14 men; age 61±15 years) were divided into three groups: patients with coadministration of L-type CCB, patients without coadministration of CCB, and patients with coadministration of sympathoinhibitory (L/T- or L/T/N-type) CCB. λ25s was calculated separately in daytime and nighttime. Results: Daytime λ25s at baseline was higher in patients with L-type CCB coadministration (0.62±0.18, n = 5) compared with those without CCB (0.49±0.13, n = 11) and those with sympathoinhibitory CCB (0.46±0.06, n = 4). The relationship between the changes in daytime λ25s and systolic blood pressure was positive in patients with L-type CCB coadministration, whereas the relationship was inverse in the other two groups. A larger decrease in daytime λ25s was shown in patients with L-type CCB coadministration compared with those in the other two groups. Conclusions: CCBs, as well as diuretics, are recommended as second-line antihypertensive agents. Our results suggested that ARBs can overwhelm the activation of sympathetic nerve activity stimulated by coadministration of L-type CCBs.

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Abstract P075: Angiotensin II Induces Endothelial Dysfunction And Vascular Remodeling Dependent Of Nlrp3 Inflammasome

Hypertension ◽

10.1161/hyp.76.suppl_1.p075 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Stefany B Cau ◽

Marcondes da Silva ◽

Nathanne d Ferreira ◽

Rita C Tostes ◽

Thiago Bruder-Nascimento

Keyword(s):

Angiotensin Ii ◽

Endothelial Dysfunction ◽

Nlrp3 Inflammasome ◽

Vascular Remodeling ◽

Vascular Diseases ◽

Vascular Damage ◽

Mesenteric Arteries ◽

Cell Counting ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

The NLRP3 inflammasome is a multimeric protein complex constituted by NLRP3, Asc and Capase-1 (Casp1). It triggers an inflammatory response by releasing the pro-inflammatory cytokines IL-1β and IL-18. NLRP3 inflammasome is expressed in different cells and its activation has been associated with several diseases including atherosclerosis and hypertension. Herein we tested the hypothesis that angiotensin II (AngII) induces vascular damage by activating the NLPR3 inflammasome in the vasculature. C57BL/6J male mice (Ctrl) and Casp-1 deficient mice (Casp1-/-) were treated with AngII (490 ng/min/kg/14 days by osmotic mini pump). In Ctrl mice, AngII treatment impaired the vascular relaxation to acetylcholine in mesenteric arteries, increased aorta media thickness [Ctrl: 49.4 ± 2.5 vs AngII: 62.3 ± 2.3* (μm), *P<0.05] and cross-sectional area [Ctrl: 0.11 ± 0.1 vs AngII: 0.15 ± 0.2* (mm), *P<0.05] and triggered NLRP3 inflammasome activation in aorta and mesenteric arteries, analyzed by caspase-1 cleavage and IL-1B maturation via western blot and casp1 activity - FAM-FLICA assay. Fascinatingly, Casp1-/- mice were protected from AngII-induced endothelial dysfunction and vascular remodeling. Furthermore, AngII (0.1uM) incubation, combined or not with lipopolysaccharide (500 ng.ml –1 ultrapure) or Nigericin (20 μM), elevated Casp1 cleavage and IL-1B maturation in Rat Aortic Smooth Muscle Cells (RASMC). Moreover, AngII elevated PCNA (~2.5-fold) and CyclinD1 (~2.1-fold) protein expression and induced vascular migration and proliferation measured by scratch assay and cell counting kit-8 (CCK-8) assay respectively. Interestingly NLRP3 antagonist incubation (MCC950, 1uM) abolished PCNA expression and attenuated the vascular migration and proliferation produced by AngII incubation. Our data suggest that AngII induces vascular damage by activating NLPR3 inflammasome directly in the vasculature. We place this innate immune receptor as a master regulator of the vascular phenotype and as a target for therapeutic strategies for vascular diseases. Future studies will be helpful providing a better understanding into the molecular mechanism of NLRP3 inflammasome activation and regulation in the control of vascular diseases.

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Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.4.h1186 ◽

1995 ◽

Vol 269 (4) ◽

pp. H1186-H1194 ◽

Cited By ~ 21

Author(s):

N. W. Morrell ◽

K. G. Morris ◽

K. R. Stenmark

Keyword(s):

Pulmonary Hypertension ◽

Angiotensin Ii ◽

Receptor Antagonist ◽

Vascular Remodeling ◽

Ace Inhibition ◽

Protective Effects ◽

Ang Ii ◽

Converting Enzyme ◽

Hypoxic Pulmonary Hypertension

Although angiotensin converting enzyme (ACE) inhibitors are known to attenuate the development of hypoxic pulmonary hypertension in rats, the precise mechanism of this protective effect remains unknown. Thus we utilized specific angiotensin II (ANG II)-receptor antagonists to investigate whether ANG II is involved directly in the hemodynamic and structural changes of pulmonary hypertension, and we tested whether the protective effects of ACE inhibition can be attributed partly to potentiation of bradykinin. During 14 days of hypobaric hypoxia, rats received, via intraperitoneal osmotic minipumps, either 1) the ACE inhibitor captopril, 2) captopril plus the bradykinin B2-receptor antagonist CP-0597, 3) the ANG II type 1 receptor antagonist losartan, 4) the ANG II type 2 receptor antagonist PD-123319, or 5) saline. At 14 days, mean pulmonary arterial pressure (MPAP) was reduced (P < 0.05) in hypoxic rats treated with captopril (26.6 +/- 0.8 mmHg) or losartan (24.4 +/- 1.0 mmHg) compared with saline (32.0 +/- 1.4 mmHg) but was unaffected by PD-123319 (29.5 +/- 1.7 mmHg). Right ventricular hypertrophy was reduced in hypoxic rats treated with captopril or losartan compared with saline-treated rats. Morphometry showed less medial thickening and peripheral muscularization of small pulmonary arteries in hypoxic animals treated with captopril or losartan. Coadministration of CP-0597 did not reverse the protective effects of captopril on pulmonary vascular remodeling. These results suggest a novel role for endogenous ANG II, acting through the type 1 receptor, in the vascular remodeling associated with hypoxic pulmonary hypertension. The beneficial effects of ACE inhibition in this model can be attributed to reduced ANG II production rather than potentiation of bradykinin.

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