2 replies to this topic

[Michael]

All:
 
Background:
 

From Wikipedia...
 
Angiotensin is a peptide hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs that raises blood pressure. Angiotensin also stimulates the release of aldosterone, another hormone, from the adrenal cortex. Aldosterone promotes sodium retention in the distal nephron, in the kidney, which also drives blood pressure up....
 
Angiotensin I is converted to angiotensin II (AII) through removal of two C-terminal residues by the enzyme angiotensin-converting enzyme (ACE) ... Angiotensin II acts on the CNS to increase ADH production, and also acts on venous and arterial vessels' smooth muscle to cause vasoconstriction. Angiotensin II also increases Aldosterone secretion, therefore, it acts as an endocrine, autocrine/paracrine, and intracrine hormone.
ACE is a target of ACE inhibitor drugs, which decrease the rate of Angiotensin II production.

 

Roles of renin-angiotensin system and Wnt pathway in aging-related phenotypes

RAS [the renin-angiotensin system] has detrimental effects on cardiovascular tissues. AT₁ receptor activation [by angiotensin II]evokes diverse G protein-dependent and G protein-independent signaling pathways, leading to cell proliferation, hypertrophic responses, apoptosis, generation of reactive oxygen species (ROS), and tissue inflammation [8]. RAS has been shown to promote the pathophysiological processes of various aging-related disorders, including not only cardiovascular diseases and heart failure but also diabetes, chronic kidney disease, dementia, osteoporosis, and cancer [9]. Recent studies have demonstrated that inhibition of RAS prolongs the physiological aging process and promotes longevity in rodents [10], suggesting the involvement of RAS in the aging process per se. ...
 
We have recently reported that RAS blockade prevented the aging-related functional decline in skeletal muscle and that this anti-aging effect of RAS blockade was associated with down-regulation of Wnt/β-catenin signaling pathway [15]. These findings suggest the relationship between RAS signaling and Wnt/β-catenin signaling in promoting aging-related phenotypes.

The news:

... Herein, I determined whether orally administrated NR could protect the aorta of middle-aged mice from acute and sustained angiotensin II (Ang II) infusion-induced damage. I demonstrate that orally administered NR can protect the aorta from damage imposed by Ang II.

Recommended Citation
Ghoreishi, Sina A., "Nicotinamide Riboside and the Aortic Response to Angiotensin II Infusion in Mice" (2017). Electronic Thesis and Dissertation Repository. 4788.
http://ir.lib.uwo.ca/etd/4788

Sounds promising. The thesis is listed as available Thursday, August 29, but in practice gives an embargoed notice; hopefully it will be available soon for inspection of the details.

[Harkijn]

Thanks for pointing this out Michael, I needed a bit of positive NR news. We will have to be patient however, because the embargo will end 29 Aug 2019! 

[Michael]

Thanks for pointing this out Michael, I needed a bit of positive NR news. We will have to be patient however, because the embargo will end 29 Aug 2019! 

 

D'oh! Well-spotted, Harkjin.

 

I've found what look to be early reports on his thesis project, from 2012 and :

 

 

Effect of a NAD+ boosting therapy on vascular stress, in vivo

Sina Ghoreishi

Supervisor: Dr. J. Geoffrey Pickering

 

I hypothesized that nicotinamide riboside administration will increase NAD+ levels in mice, imparting resistance to angiotensin II-mediated vascular stress. To test this, middle aged (6 months) C57Bl/6 mice received NR (400mg/kg/day) or vehicle (chow) treatment for a total of seven weeks. At three weeks, vascular stress was induced by continuous angiotensin II (1.44 mg/kg/day) infusion for four weeks.

 

After seven weeks, livers of NR-treated mice had 3.2-fold higher NAD+ content (p<.05).

 

NR did not demonstrably impact basal blood pressure over 3 weeks of administration. The effects of NR on angiotensin II-induced hypertension appeared to be strain specific. NR-treated mice provided by Charles River showed a trend towards reduced mean arterial pressure (MAP) after 28 days of angiotensin II infusion, whereas MAP in NR-treated mice from Jackson Laboratories tended to be higher in response to angiotensin II.

 

Angiotensin II resulted in DNA damage, as indicated by 8-Oxo-2'-deoxyguanosine (8-oxo-dG) formation in endothelial, smooth muscle and adventitial cells in the aorta. Perivascular collagen deposition & fibrosis was also observed in hearts after angiotensin II infusion. Interestingly, 2 of 7 chow-treated mice exhibited severe fibrosis, 10-fold greater than what was observed in NR-treated mice.

 

Together these data have identified diverse cardiovascular abnormalities in response to angiotensin II infusion, some of which may be influenced by NR in a strain dependent manner. Future work will involve evaluation of these findings in more animals (increased sample size) and the investigation of additional markers of endothelial cell stress and function.

 

Notes: I am not a renal physiologist, and can't say how physiologic the dose of AngII is: lots of studies use doses this high or higher for acute studies, but we'd want a dose that reflects either hypertensive patients or "normal" aging. This study first recorded "The basal systolic blood pressure and the pressure responses against intraperitoneal injection of angiotensin II (10 and 30 μg/kg) ... prior to the administration of captopril [an ACE inhibitor, which blocks AngII production], and then "After the administration of captopril (500 mg/liter in drinking water) for 1 week to inhibit the endogenous production of angiotensin II, the pressure responses to angiotensin II given from lower dose (3–30 μg/kg) were recorded," suggesting that 3-30 µg may be a more physiological dose — hundreds of times lower than that used in this study.

 

The difference in responses by mouse origin is interesting. My first reaction was that since they specify the use of "C57Bl/6 mice," but not the substrain, the responsive mice might have been C57BL/6J and the unresponsive mice some other substrain that does not have the NNT mutation — but the responsive mice were from Charles River, and the unresponsive mice from The Jackson Laboratories, and you'd be more likely to get "Js" from Jackson than from CR.

 

Only 7 mice, and only 2 with fibrosis to detect a difference ...! Yes, let's hope he got a lot more mice.

 

Another abstract says:

 

 

Nicotinamide riboside did not impact basal blood pressure over 3 weeks of administration. However, NR treated mice experienced a smaller increase in mean arterial pressure in response to 28 day angiotensin II infusion. Histological analysis revealed hemorrhage in the ascending aorta of 2/3 vehicle-treated mice, while 0/3 NR treated mice displayed this phenotype. Our preliminary results suggest that NR has a protective effect against vascular stress. Future work is underway to increase sample size and quantify NAD+ levels in vascular tissue.

 

The smaller numbers (2 of 3 vs. 2 of 7) and the blanket statement on response to AngII-inducd hypertension seem to suggest that this was earlier than the above, and when he added a few mice from a different source he got a different result.