Angiotensin II-Induced Cardiovascular Fibrosis Is Attenuated by NO-Sensitive Guanylyl Cyclase1

Abstract

In the NO/cGMP signaling cascade, relevant in the cardiovascular system, two NO-sensitive guanylyl cyclase (NO-GC) isoforms are responsible for NO-dependent cGMP generation. Here, the impact of the major NO-GC isoform, NO-GC1, on fibrosis development in the cardiovascular system was studied in NO-GC1-deficient mice treated with AngiotensinII (AngII), known to induce vascular and cardiac remodeling. Morphometric analysis of NO-GC1 KO’s aortae demonstrated an enhanced increase of perivascular area after AngII treatment accompanied by a higher aortic collagen1 mRNA content. Increased perivascular fibrosis also occurred in cardiac vessels of AngII-treated NO-GC1 KO mice. In line, AngII-induced interstitial fibrosis was 32% more pronounced in NO-GC1 KO than in WT myocardia associated with a higher cardiac Col1 and other fibrotic marker protein content. In sum, increased perivascular and cardiac interstitial fibrosis together with the enhanced collagen1 mRNA content in AngII-treated NO-GC1-deficient mice represent an exciting manifestation of antifibrotic properties of cGMP formed by NO-GC1, a finding with great pharmaco-therapeutic implications.

Inorganic nitrate attenuates cardiac dysfunction: roles for xanthine oxidoreductase and nitric oxide

“…In addition to the effects upon cardiac function, dietary nitrate also exerted anti‐fibrotic effects. Our data fit well with previous data demonstrating that low levels of NO interfere with SMAD phosphorylation and its consequent nuclear localisation (Saura et al, 2005), an effect linked with elevations in cGMP and PKG activity (Sandner & Stasch, 2017), most likely due to actions on NO‐sensitive fibroblasts, rather than directly on cardiac myocytes (Broekmans et al, 2020; Menges et al, 2019) and fits with the data demonstrating no change in cardiomyocyte size with dietary nitrate in either intervention, despite the decreases in LV mass. Recent studies in rats have demonstrated that inorganic nitrite treatment reduces l ‐NAME‐induced cardiac fibrosis (Sonoda et al, 2017), an effect linked to reductions in ANGII and AT 1 receptor expression—a key remodelling pathway that is activated particularly in hypertensive heart disease (Berk et al, 2007).…”

The Interplay of Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress in Cardiovascular Fibrosis in Obese Rats

“…These effects were accompanied by an attenuation of ER stress at cardiac and vascular levels. In addition, ROS reduction and ER stress inhibition by MitoQ or 4-PBA, respectively, reduced the profibrotic actions of Ang II, whose levels are elevated in obese animals and involved in cardiovascular fibrosis associated with obesity in cardiac and vascular cells [ 35 , 36 ]. This suggests that interactions between ER stress and mitochondrial oxidative stress regulate downstream events and are responsible for fibrosis in the context of obesity.…”

“…Inhibition of mitochondrial oxidative stress with MitoQ prevented all of these alterations, thus supporting the role of ER stress in the profibrotic effect of mitochondrial oxidative stress in the context of obesity. Moreover, there seems to be a crosstalk between mitochondrial oxidative stress and ER stress activation, which mediates the increase in ECM proteins, ROS production and ER stress activation in Ang II-treated cardiovascular cells, a factor involved in the cardiovascular fibrosis associated with obesity [ 36 , 71 ].…”

The pro‐resolving mediator, annexin A1 regulates blood pressure, and age‐associated changes in cardiovascular function and remodeling

“…LV sections were stained with hematoxylin and eosin to measure cardiomyocyte area and width using a semi‐automated macro in Image J software (version 1.53c, National Institute of Health, USA) 52 . Verhoeff–van Gieson (VVG) stain identified elastin 54 and Von Kossa stain indicated calcium deposition 55 in vessels. Stained colors relevant to elastin content and calcium area in the vessel were extracted using trained Ilastik models 56 in Image J software (version 1.53c, National Institute of Health, USA).…”