1. Gut microbiota dependent trimethylamine N-oxide aggravates angiotensin II-induced hypertension
Shan Jiang, et al. Redox Biol. 2021 Oct;46:102115. doi: 10.1016/j.redox.2021.102115. Epub 2021 Aug 25.
Gut microbiota produce Trimethylamine N-oxide (TMAO) by metabolizing dietary phosphatidylcholine, choline, l-carnitine and betaine. TMAO is implicated in the pathogenesis of chronic kidney disease (CKD), diabetes, obesity and atherosclerosis. We test, whether TMAO augments angiotensin II (Ang II)-induced vasoconstriction and hence promotes Ang II-induced hypertension. Plasma TMAO levels were indeed elevated in hypertensive patients, thus the potential pathways by which TMAO mediates these effects were explored. Ang II (400 ng/kg-1min-1) was chronically infused for 14 days via osmotic minipumps in C57Bl/6 mice. TMAO (1%) or antibiotics were given via drinking water. Vasoconstriction of renal afferent arterioles and mesenteric arteries were assessed by microperfusion and wire myograph, respectively. In Ang II-induced hypertensive mice, TMAO elevated systolic blood pressure and caused vasoconstriction, which was alleviated by antibiotics. TMAO enhanced the Ang II-induced acute pressor responses (12.2 ± 1.9 versus 20.6 ± 1.4 mmHg; P < 0.05) and vasoconstriction (32.3 ± 2.6 versus 55.9 ± 7.0%, P < 0.001). Ang II-induced intracellular Ca2+ release in afferent arterioles (147 ± 7 versus 234 ± 26%; P < 0.001) and mouse vascular smooth muscle cells (VSMC, 123 ± 3 versus 157 ± 9%; P < 0.001) increased by TMAO treatment. Preincubation of VSMC with TMAO activated the PERK/ROS/CaMKII/PLCβ3 pathway. Pharmacological inhibition of PERK, ROS, CaMKII and PLCβ3 impaired the effect of TMAO on Ca2+ release. Thus, TMAO facilitates Ang II-induced vasoconstriction, thereby promoting Ang II-induced hypertension, which involves the PERK/ROS/CaMKII/PLCβ3 axis.
2. Association amongst human A1166C polymorphism of the angiotensin II type 1 receptor gene with coronary artery disease in the Iraqi population
Mazin Thamir Abdul-Hasan, Ali M Omara, Dhafer A F Al-Koofee J Diabetes Metab Disord. 2022 Apr 21;21(1):727-733. doi: 10.1007/s40200-022-01041-z. eCollection 2022 Jun.
Purpose: Coronary artery disease (CAD) is a major cause of death worldwide. There is relatively little data available on the genetic susceptibility to CAD in the Iraqi population. We have therefore investigated the association between angiotensin II type 1 receptor gene polymorphism A1166C and the presence of CAD in a sample of the Iraqi population. Methods: This case-control study enrolled 150 CAD patients, with CAD confirmed by coronary angiography, and 200 controls. The AT1R polymorphism A1166C was analyzed by the allele-specific polymerase chain reaction (AS-PCR) technique. Serum analyses, such as lipid concentrations, were measured and analyzed. Results: The C allele and CC genotype frequencies were significantly higher in patients with CAD compared to the controls. Logistic regression analysis showed that the codominant, dominant, and recessive models were associated with risk of CAD of (OR = 1.32, 95% CI: 1.2-1.4, P = 0.000; OR = 1.25, 95% CI: 1.1-1.3, P = 0.000, OR = 1.27, 95% CI: 1.1-1.3, P = 0.000, OR = 1.18, 95% CI: 1.0-1.4), respectively. In the patient group, the presence of the mutant C allele was significantly associated with higher levels of CAD risk factors such as total cholesterol (TC) and low-density lipoprotein (LDL). Conclusion: The study indicated that the A1166C polymorphism may be associated with the presence of CAD in the Iraqi population. The AT1R polymorphism may therefore be a useful marker of susceptibility to CAD.
3. Telmisartan, ramipril, or both in patients at high risk for vascular events
ONTARGET Investigators, et al. N Engl J Med. 2008 Apr 10;358(15):1547-59. doi: 10.1056/NEJMoa0801317. Epub 2008 Mar 31.
Background: In patients who have vascular disease or high-risk diabetes without heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and morbidity from cardiovascular causes, but the role of angiotensin-receptor blockers (ARBs) in such patients is unknown. We compared the ACE inhibitor ramipril, the ARB telmisartan, and the combination of the two drugs in patients with vascular disease or high-risk diabetes. Methods: After a 3-week, single-blind run-in period, patients underwent double-blind randomization, with 8576 assigned to receive 10 mg of ramipril per day, 8542 assigned to receive 80 mg of telmisartan per day, and 8502 assigned to receive both drugs (combination therapy). The primary composite outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. Results: Mean blood pressure was lower in both the telmisartan group (a 0.9/0.6 mm Hg greater reduction) and the combination-therapy group (a 2.4/1.4 mm Hg greater reduction) than in the ramipril group. At a median follow-up of 56 months, the primary outcome had occurred in 1412 patients in the ramipril group (16.5%), as compared with 1423 patients in the telmisartan group (16.7%; relative risk, 1.01; 95% confidence interval [CI], 0.94 to 1.09). As compared with the ramipril group, the telmisartan group had lower rates of cough (1.1% vs. 4.2%, P<0.001) and angioedema (0.1% vs. 0.3%, P=0.01) and a higher rate of hypotensive symptoms (2.6% vs. 1.7%, P<0.001); the rate of syncope was the same in the two groups (0.2%). In the combination-therapy group, the primary outcome occurred in 1386 patients (16.3%; relative risk, 0.99; 95% CI, 0.92 to 1.07); as compared with the ramipril group, there was an increased risk of hypotensive symptoms (4.8% vs. 1.7%, P<0.001), syncope (0.3% vs. 0.2%, P=0.03), and renal dysfunction (13.5% vs. 10.2%, P<0.001). Conclusions: Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema. The combination of the two drugs was associated with more adverse events without an increase in benefit. (ClinicalTrials.gov number, NCT00153101 [ClinicalTrials.gov].).
