Pleiotropic activation of endothelial function by angiotensin II receptor blockers is crucial to their protective anti-vascular remodeling effects

Abstract

There are no therapeutics that directly enhance chronic endothelial nitric oxide (NO) release, which is typically associated with vascular homeostasis. In contrast, angiotensin II (AngII) receptor type 1 (AT1R) blockers (ARBs) can attenuate AngII-mediated oxidative stress, which often leads to increased endothelial NO bioavailability. Herein, we investigate the potential presence of direct, AngII/AT1R-independent ARB class effects on endothelial NO release and how this may result in enhanced aortic wall homeostasis and endothelial NO-specific transcriptome changes. Treatment of mice with four different ARBs induced sustained, long-term inhibition of vascular contractility by up to 82% at 16 weeks and 63% at 2 weeks, an effect reversed by L-NAME and absent in endothelial NO synthase (eNOS) KO mice or angiotensin converting enzyme inhibitor captopril-treated animals. In absence of AngII or in tissues with blunted AT1R expression or incubated with an AT2R blocker, telmisartan reduced vascular tone, supporting AngII/AT1R-independent pleiotropism. Finally, telmisartan was able to inhibit aging- and Marfan syndrome (MFS)-associated aortic root widening in NO-sensitive, BP-independent fashions, and correct aberrant TGF-β signaling. RNAseq analyses of aortic tissues identified early eNOS-specific transcriptome reprogramming of the aortic wall in response to telmisartan. This study suggests that ARBs are capable of major class effects on vasodilatory NO release in fashions that may not involve blockade of the AngII/AT1R pathway. Broader prophylactic use of ARBs along with identification of non-AngII/AT1R pathways activated by telmisartan should be investigated.

Endothelial dysfunction in Marfan syndrome mice is restored by resveratrol

“…( 1234567890 MFS patients are often prescribed angiotensin-II receptor blockers (ARBs), of which losartan is most commonly used. Interestingly, ARBs have also been shown to have an angiotensin-II receptor independent protective function involving enhancement of EC function 32,86,87 , although treatment effects are diverse over the various FBN1 genotypes 88 and for the various ARBs 89 . Moreover, ARBs were effective in reducing aneurysm formation in angiotensin-II receptor deficient mice by targeting EC function 32 .…”

Angiotensin-Converting Enzyme and Hypertension: A Systemic Analysis of Various ACE Inhibitors, Their Side Effects, and Bioactive Peptides as a Putative Therapy for Hypertension

“…ACE expression is found in the capillaries of the lungs and also in the endothelium of the kidney. It is necessary for the regulation of blood pressure and electrolyte homeostasis throughout the renin-angiotensin system [41]. RAS is the central monitor of arterial blood pressure, and ACE is one of its main regulators whose role is to convert the decapeptide angiotensin to an octapeptide angiotensin II [42], Ang-(1-9) to Ang-(1-7), and then other degrade its peptide to the inactive Ang- (1)(2)(3)(4)(5).…”

“…The activity of somatic ACE is highly dependent on the chloride ion concentration and is immobile in its deficiency, whereas the N domain is completely active at relatively low concentrations or even in the absence of chloride ions [65]. Somatic ACE has two diverse domains C and D, and each contains an observant active site [41]. Both of these domains are involved in Ang I formation and bradykinin degradation; therefore, both of these domains are important in systolic blood pressure regulation and cardiac stroke.…”

“…The soluble form of ACE, different from the membrane-bound form, is formed due to the ACE secretase action and is found in serum and other body fluids. Testicular ACE is the ancestral form of the molecule with a particular active site; its crystal structure was published in 2003 [41]. Somatic ACE arose as an implication of gene duplication and contains two active sites (Terminal N- and C-domains).…”

Vascular homeostasis in atherosclerosis: A holistic overview

“…To this end, several categories of drugs are able to stabilize the “vascular niche” ( 51 ) and prevent atherosclerosis ( Figure 2B ). These drugs include statins (lipid-lowering drugs) ( 52 ), Angptl3 inhibitors ( 53 ), ACLY inhibitors (such as Bempedoic acid) ( 54 ), gliflozins (SGLT2 inhibitors, anti-diabetic drugs) ( 55 ), glutides (GLP-1 receptor agonists, anti-diabetic drugs) ( 56 ), metformin (anti-diabetic drugs) ( 57 – 59 ), aspirin (COX inhibitor, NSAIDs), Angiotensin II converting enzyme inhibitors (ACEI, anti-hypertensive drugs) ( 60 ), Angiotensin II receptor blockers (ARBs, anti-hypertensive drugs) ( 60 , 61 ), naturally-occurring NLRP3 inflammasome inhibitor (colchicine) ( 62 ), KLF2 activators ( 63 , 64 ), AMPK activators (endothelial protective drugs) ( 65 ) and many others. Based on the complex nature of atherosclerosis, polypill or ploypharmacology targeting established mechanisms/risk factors are needed.…”