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Role of T lymphocytes in angiotensin II-mediated microvascular thrombosis.

ABSTRACT: Clinical trials and animal studies have revealed a role for the renin-angiotensin system in the enhanced thrombus development that is associated with hypertension. Because T lymphocytes have been implicated in the vascular dysfunction and blood pressure elevation associated with increased angiotensin II (Ang II) levels, we evaluated the role of the adaptive immune system in mediating the enhanced thrombosis during Ang II-induced hypertension. Light/dye-induced thrombosis was induced in cremaster arterioles of wild-type, immunodeficient Rag-1(-/-), CD8(+), or CD4(+) lymphocyte-deficient and NADPH oxidase (gp91(phox))-deficient mice implanted with an Ang II-loaded pump for 2 weeks. Chronic Ang II infusion enhanced arteriolar thrombosis in wild-type mice but not in Rag-1(-/-), CD4(+) T-cell-deficient, or gp91(phox-/-) mice. CD8(+) T-cell(-/-) mice exhibited partial protection. Adoptive transfer of T cells derived from wild-type or gp91(phox-/-) mice into Rag-1(-/-) restored the prothrombotic phenotype induced by Ang II. T lymphocytes (CD4(+) and, to a lesser extent, CD8(+)) play a major role in mediating the accelerated microvascular thrombosis associated with Ang II-induced hypertension. NADPH oxidase-derived reactive oxygen species, produced by cells other than T lymphocytes, also appear critical for the Ang II-enhanced, T cell-dependent thrombosis response.

SUBMITTER: Senchenkova EY

PROVIDER: S-EPMC3199307 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Role of T lymphocytes in angiotensin II-mediated microvascular thrombosis.

Senchenkova Elena Y EY Russell Janice J Kurmaeva Elvira E Ostanin Dmitry D Granger D Neil DN

Hypertension (Dallas, Tex. : 1979) 20110912 5

Clinical trials and animal studies have revealed a role for the renin-angiotensin system in the enhanced thrombus development that is associated with hypertension. Because T lymphocytes have been implicated in the vascular dysfunction and blood pressure elevation associated with increased angiotensin II (Ang II) levels, we evaluated the role of the adaptive immune system in mediating the enhanced thrombosis during Ang II-induced hypertension. Light/dye-induced thrombosis was induced in cremaster ...[more]

PMID: 21911709

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Project description:AimsAngiotensin II (AngII) is a potent vasoconstrictor implicated in both hypertension and insulin resistance. Insulin dilates the vasculature in skeletal muscle to increase microvascular blood flow and enhance glucose disposal. In the present study, we investigated whether acute AngII infusion interferes with insulin's microvascular and metabolic actions in skeletal muscle.Methods and resultsAdult, male Sprague-Dawley rats received a systemic infusion of either saline, AngII, insulin (hyperinsulinaemic euglycaemic clamp), or insulin (hyperinsulinaemic euglycaemic clamp) plus AngII. A final, separate group of rats received an acute local infusion of AngII into a single hindleg during systemic insulin (hyperinsulinaemic euglycaemic clamp) infusion. In all animals' systemic metabolic effects, central haemodynamics, femoral artery blood flow, microvascular blood flow, and skeletal muscle glucose uptake (isotopic glucose) were monitored. Systemic AngII infusion increased blood pressure, decreased heart rate, and markedly increased circulating glucose and insulin concentrations. Systemic infusion of AngII during hyperinsulinaemic euglycaemic clamp inhibited insulin-mediated suppression of hepatic glucose output and insulin-stimulated microvascular blood flow in skeletal muscle but did not alter insulin's effects on the femoral artery or muscle glucose uptake. Local AngII infusion did not alter blood pressure, heart rate, or circulating glucose and insulin. However, local AngII inhibited insulin-stimulated microvascular blood flow, and this was accompanied by reduced skeletal muscle glucose uptake.ConclusionsAcute infusion of AngII significantly alters basal haemodynamic and metabolic homeostasis in rats. Both local and systemic AngII infusion attenuated insulin's microvascular actions in skeletal muscle, but only local AngII infusion led to reduced insulin-stimulated muscle glucose uptake. While increased local, tissue production of AngII may be a factor that couples microvascular insulin resistance and hypertension, additional studies are needed to determine the molecular mechanisms responsible for these vascular defects.

Project description:Background and purposeMitochondrial dysfunction plays a role in the progression of cardiovascular diseases including heart failure. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins), which inhibit ROS synthesis, show cardioprotective effects in chronic heart failure. However, the beneficial role of statins in mitochondrial protection in heart failure remains unclear.Experimental approachRats were treated with angiotensin II (1.5 mg·kg-1 ·day-1 ) or co-administered simvastatin (oral, 10 mg·kg-1 ) for 14 days; and then administration was stopped for the following 14 days. Cardiac structure/function was examined by wheat germ agglutinin staining and echocardiography. Mitochondrial morphology and the numbers of lipid droplets, lysosomes, autophagosomes, and mitophagosomes were determined by transmission electron microscopy. Human cardiomyocytes were stimulated, and intracellular ROS and mitochondrial membrane potential (ΔΨm ) changes were measured by flow cytometry and JC-1 staining, respectively. Autophagy and mitophagy-related and mitochondria-regulated apoptotic proteins were identified by immunohistochemistry and western blotting.Key resultsSimvastatin significantly reduced ROS production and attenuated the disruption of ΔΨm . Simvastatin induced the accumulation of lipid droplets to provide energy for maintaining mitochondrial function, promoted autophagy and mitophagy, and inhibited mitochondria-mediated apoptosis. These findings suggest that mitochondrial protection mediated by simvastatin plays a therapeutic role in heart failure prevention by modulating antioxidant status and promoting energy supplies for autophagy and mitophagy to inhibit mitochondrial damage and cardiomyocyte apoptosis.Conclusion and implicationsMitochondria play a key role in mediating heart failure progression. Simvastatin attenuated heart failure, induced by angiotensin II, via mitochondrial protection and might provide a new therapy to prevent heart failure.

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Role of T lymphocytes in angiotensin II-mediated microvascular thrombosis.

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Role of T lymphocytes in angiotensin II-mediated microvascular thrombosis.

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