biostudies-literatureMatsumura SNHLBI NIH HHS107002https://www.ebi.ac.uk/biostudies/studies/S-EPMC9728130biostudies-literatureUnknown145<h4>Rationale</h4>Epidemiological studies suggest that individuals in the Mediterranean region with deficiency of glucose-6-phosphate dehydrogenase (G6PD) are less susceptible to cardiovascular diseases. However, our knowledge regarding the effects of G6PD deficiency on pathogenesis of vascular diseases caused by factors, like angiotensin II (Ang-II), which stimulate synthesis of inflammatory cytokines and vascular inflammation, is lacking. Furthermore, to-date the effect of G6PD deficiency on vascular health has been controversial and difficult to experimentally prove due to a lack of good animal model.<h4>Objective</h4>To determine the effect of Ang-II-induced hypertension (HTN) and stiffness in a rat model of the Mediterranean G6PD (G6PD^S188F) variant and in wild-type (WT) rats.<h4>Methods and results</h4>Our findings revealed that infusion of Ang-II (490 ng/kg/min) elicited less HTN and medial hypertrophy of carotid artery in G6PD^S188F than in WT rats. Additionally, Ang-II induced less glomerular and tubular damage in the kidneys - a consequence of elevated pressure - in G6PD^S188F than WT rats. However, Ang-II-induced arterial stiffness increased in G6PD^S188F and WT rats, and there were no differences between the groups. Mechanistically, we found aorta of G6PD^S188F as compared to WT rats produced less sustained contraction and less inositol-1,2,3-phosphate (IP3) and superoxide in response to Ang-II. Furthermore, aorta of G6PD^S188F as compared to WT rats expressed lower levels of phosphorylated extracellular-signal regulated kinase (ERK). Interestingly, the aorta of G6PD^S188F as compared to WT rats infused with Ang-II transcribed more (50-fold) myosin heavy chain-11 (MYH11) gene, which encodes contractile protein of smooth muscle cell (SMC), and less (2.3-fold) actin-binding Rho-activating gene, which encodes a protein that enhances SMC proliferation. A corresponding increase in MYH11 and Leiomodin-1 (LMOD1) staining was observed in arteries of Ang-II treated G6PD^S188F rats. However, G6PD deficiency did not affect the accumulation of CD45⁺ cells and transcription of genes encoding interleukin-6 and collagen-1a1 by Ang-II.<h4>Conclusions</h4>The G6PD^S188F loss-of-function variant found in humans protected rats from Ang-II-induced HTN and kidney damage, but not from vascular inflammation and arterial stiffness.Vascular pharmacologyMediterranean G6PD variant rats are protected from Angiotensin II-induced hypertension and kidney damage, but not from inflammation and arterial stiffness.PMC9728130K01 HL145324R01 HL132574De Miguel CMiano JMGupte RStier CGupte SAMatsumura SD'Addiaro CSlivano OJfalseMediterranean G6PD variant rats are protected from Angiotensin II-induced hypertension and kidney damage, but not from inflammation and arterial stiffness.<h4>Rationale</h4>Epidemiological studies suggest that individuals in the Mediterranean region with deficiency of glucose-6-phosphate dehydrogenase (G6PD) are less susceptible to cardiovascular diseases. However, our knowledge regarding the effects of G6PD deficiency on pathogenesis of vascular diseases caused by factors, like angiotensin II (Ang-II), which stimulate synthesis of inflammatory cytokines and vascular inflammation, is lacking. Furthermore, to-date the effect of G6PD deficiency on vascular health has been controversial and difficult to experimentally prove due to a lack of good animal model.<h4>Objective</h4>To determine the effect of Ang-II-induced hypertension (HTN) and stiffness in a rat model of the Mediterranean G6PD (G6PD^S188F) variant and in wild-type (WT) rats.<h4>Methods and results</h4>Our findings revealed that infusion of Ang-II (490 ng/kg/min) elicited less HTN and medial hypertrophy of carotid artery in G6PD^S188F than in WT rats. Additionally, Ang-II induced less glomerular and tubular damage in the kidneys - a consequence of elevated pressure - in G6PD^S188F than WT rats. However, Ang-II-induced arterial stiffness increased in G6PD^S188F and WT rats, and there were no differences between the groups. Mechanistically, we found aorta of G6PD^S188F as compared to WT rats produced less sustained contraction and less inositol-1,2,3-phosphate (IP3) and superoxide in response to Ang-II. Furthermore, aorta of G6PD^S188F as compared to WT rats expressed lower levels of phosphorylated extracellular-signal regulated kinase (ERK). Interestingly, the aorta of G6PD^S188F as compared to WT rats infused with Ang-II transcribed more (50-fold) myosin heavy chain-11 (MYH11) gene, which encodes contractile protein of smooth muscle cell (SMC), and less (2.3-fold) actin-binding Rho-activating gene, which encodes a protein that enhances SMC proliferation. A corresponding increase in MYH11 and Leiomodin-1 (LMOD1) staining was observed in arteries of Ang-II treated G6PD^S188F rats. However, G6PD deficiency did not affect the accumulation of CD45⁺ cells and transcription of genes encoding interleukin-6 and collagen-1a1 by Ang-II.<h4>Conclusions</h4>The G6PD^S188F loss-of-function variant found in humans protected rats from Ang-II-induced HTN and kidney damage, but not from vascular inflammation and arterial stiffness.2022-01-01T00:00:00Z2022 Aug2025-04-19T05:54:17.947Z2025-04-19T05:54:17.947ZS-EPMC97281303562354610.1016/j.vph.2022.107002