DKK-1 Enhances Inflammatory Interaction Between Platelets and Endothelial Cells and Shows Increased Expression in Atherosclerosis.

Arterioscler Thromb Vasc Biol. 2009 Jun 4.
Dickkopf-1 Enhances Inflammatory Interaction Between Platelets and Endothelial Cells and Shows Increased Expression in Atherosclerosis.
Ueland T, Otterdal K, Lekva T, Halvorsen B, Gabrielsen A, Sandberg WJ, Paulsson-Berne G, Pedersen TM, Folkersen L, Gullestad L, Oie E, Hansson GK, Aukrust P.

Research Institute for Internal Medicine, the Department of Endocrinology, the Department of Cardiology, and the Section of Clinical Immunology and Infectious Diseases, Rikshospitalet, Oslo University Hospital, and the Faculty of Medicine, University of Oslo, Norway; and the Centre for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.

OBJECTIVE: Based on the emerging importance of the wingless (Wnt) pathways in inflammation and vascular biology, we hypothesized a role for Dickkopf-1 (DKK-1), a major modulator of Wnt signaling, in atherogenesis and plaque destabilization. METHODS AND RESULTS: We report increased levels of DKK-1 in experimental (ApoE(-/-) mice) and clinical (patients with coronary artery disease [n=80] and patients with carotid plaque [n=47]) atherosclerosis, both systemically (serum) and within the lesion, with particularly high levels in advanced and unstable disease. We identified platelets as an important cellular source of DKK-1 as shown by in vitro experiments and by immunostaining of thrombus material obtained at the site of plaque rupture in patients with acute ST-elevation myocardial infarction, with strong immunoreactivity in platelet aggregates. Our in vitro experiments identified a role for platelet- and endothelial-derived DKK-1 in platelet-dependent endothelial activation, promoting enhanced release of inflammatory cytokines. These inflammatory effects of DKK-1 involved inhibition of the Wnt/beta-catenin pathway and activation of nuclear factor kappaB. CONCLUSIONS: Our findings identify DKK-1 as a novel mediator in platelet-mediated endothelial cell activation. The demonstration of enhanced DKK-1 expression within advanced carotid plaques may suggest that this DKK-1-driven inflammatory loop could be operating within the atherosclerotic lesion.

dickkopf 1 (DKK-1) is one of the most upregulated genes in balding dermal papilla cells. With all the casual associations
between cardiovascular diseases and male pattern baldness, maybe it's no surprise that DKK-1 is implicated in atherosclerosis.

Generally it's perfectly normal to have DKK-1 proteins in areas on the skin that are non intended to possess hair, such as the palm of the hand or the bottom of feet.

Looking for a way this can epigenetically silenced or inhibited in a convenient fashion.

The target is probably apolipoprotein(a), also known as Lipoprotein-a or Lp(a). This is linked to increased DKK-1.

Found a patent on Lp(a) reduction and hair loss prevention.

http://www.freepatentsonline.com/5741514.html

*thumbs up*

Ecklonia Cava is implicated here, correct?

Or are there other supps that target this pathway?

Here's a few highlights from the patent:

In another aspect, the invention includes a method of achieving hair regrowth in a person suffering from male pattern baldness or alopecia, and a method of improving the periodontal condition in a person having symptoms of periodontal disease, such as gingivitis, tooth mobility or bone loss.

Hair Regrowth

In another aspect, the invention includes a method of improving hair regrowth in a person having alopecia or male pattern baldness.

An elderly male subject with scalp hair loss was treated with liposomes, administered according to the dosing schedule described in Example 3. The subject noticed a significant improvement in hair regrowth after liposome treatment.

In a nutshell, this patent discusses the intravenous use of Egg derived Phosphatidylcholine.

In integrative medicine this is still used today, it was originated patented in Europe--but it's known today as Plaquex. It's known as essential phospholipid therapy or the use of IV-EPL.

However, there is an alternative to intravenous essential phospholipids. It's not lecithin, because the micelles cannot accept all that much lecithin within the blood stream, but this product below is specially processed to allow the essential phospholipids to enter into the blood stream. This product is normally intended to clean out arteries and remove out the plaque.

http://www.iherb.com/Allergy-Research-Group-Nutricology-LipoPhos-Forte-4-fl-oz-120-ml/7785?at=0

Of course there are several other ways to remove plaque, but the focus here is Lp(a). Some ways involve high dose Niacin, Co-Enzyme Q10

If Lp(a) really has a direct influence on DKK-1, this could be an important target for MPB. Lp(a) is already a very significant risk factor in heart disease so lowering this would be of great value.

In an earlier thread Espio posted this:

http://web.inonu.edu.tr/~msenol/androgenetik.pdf

A quote:

"The most remarkable result of our study is the significantly
higher levels of Lp(a) in patients with
androgenetic alopecia because Lp(a) is an important,
independent and genetically determined risk factor for
coronary heart disease [2]. It has been shown that high
levels of Lp(a) in men under 56 years was a strong
indicator of angiographically confirmed CHD [5]."

There's still quite a lot that is not known about what Lp(a) does in the body. It's suspected it might play a
role in wound healing, but it's also implicated in plaque formation.

There was a study that showed that a moderate consumption of alcohol lowered Lp(a), but it didn't occur
world wide--probably has to do with what is actually used to drink. Red wine is probably best.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1113249

halfempty - Ecklonia Cava inhibits oxidation of "regular" LDL or low density lipoproteins and may inhibit the absorption of them, but unfortunately it's not related to Lp(a).

Hey CausticSymmetry,

While I know it won't be as effective as the product you linked to, LipoPhos Forte, but will the
phospholipids in krill oil enter the bloodstream and reduce Lp(a) eventually?


Thanks

jdp710 - Thanks for pointing this out--totally forgot to check this out.

From what I've read, 1,000 milligrams of Krill oil can reduce Lp(a) levels up to 25%.

there's an interesting relation between DKK-1 and calcium deposition but it looks like Lp(a) doesn't play a role in calcium deposition
http://www.news-medical.net/news/2005/04/05/8992.aspx
http://endo.endojournals.org/cgi/content/full/149/4/1793

and IH you might like this study about DKK-1 and lithium chloride
http://www.jbc.org/cgi/content/full/M406275200

I've been going at hair loss at the Lp(a) route for about a month and a half. I've been taking this every day:

1000 mg krill oil
1500 mg niacin
3000 mg vitamin C

I've also been trying to eat more fruits, vegetables, and nuts, which also helps to lower it.

I just looked at some pictures today and my hair is pretty much the same as it was in January, 5 months ago. So something is working, because it was thinning heavily before January. So I don't know if it was the lower Lp(a) or what, but whatever I did has worked.

Hey Caustic Symmetry or anyone else,

I've looked everywhere to find an answer but to no avail. If you could answer this question it would be much appreciated ...

Is their a correlation between C-Reactive Protein levels and Lp(a)? What I'm essentially wondering is would lowering CRP levels also lower Lp(a)?

BTW, this was interesting that eradicating H Pylori lowers Lp(a)

===============================================

Abstract
Helicobacter pylori has been implicated in the cardiovascular risk of diabetic patients. The aimof our study was to investigate whether the Helicobacter pylori infection plays a role in the lipid and haemostasis patterns of type 1 diabetic patients. Twenty nine patients with type 1 diabetes mellitus and H. pylori infection were enrolled (Chlamydia pneumoniae negative). The H. pylori infection status was assessed by serology and urease breath test. In all patients levels of total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, lipoprotein (a) (Lpa) C reactive protein (CRP), fibrinogen, thrombin/antithrombin III complex (TAT), plasminogen activator inhibitor type 1(PAI-1), tissue plasminogen activator (t-PA) and von Willebrand antigen were measured. All patients were evaluated before and after H. pylori eradicating treatment with amoxicillin, clarithromycin and omeprazole. Twenty two patients were eradicated and seven remained infected.

In H. pylori eradicated patients, HDL cholesterol increased (59.7±18.9 mg/dl vs 65.2±15.9 mg/dl, P < 0.05) and lipoprotein (a) decreased (23.1±14.0 mg/dl vs 18.3±12.3 mg/dl, P < 0.05), after treatment. After H. pylori eradication, the levels of CRP and TAT decreased (48±0.7 ng/l vs 3.3±0.4 ng/l; P < 0.05), (27.7±44.7 μg/ml vs 2.1±1.4 μg/ml, P < 0.05), respectively. The decrease in TAT was higher in the group of H. pylori (+) patients with higher levels of TAT (TAT > 20 ng/ml, 92.8±41.6 ng/ml vs 1.9±2.0 ng/ml, P < 0.005; TAT 4-20 ng/ml; 10.1±5.2 ng/ml vs 2.2±0.6 ng/ml, P < 0.05). These changes did not occur in patients without H. pylori eradication. Eradication of H. pylori infection in type 1 diabetic patients modifies some parameters of lipid and haemostasis patterns, (increase of HDL-cholesterol, reduction of Lpa and decrease of CRP and TAT) and so contributes to improvement of cardiovascular risk factors in these patients

The presence of Wnt signalling inhibitors such as Dkk-1 (Glinka et al, 1998; Krupnik et al, 1999; Nusse, 2001; Mao et al, 2002; Kawano and Kypta, 2003; Li et al, 2006; Morvan et al, 2006) can disrupt the repair of bone and its secretion by tumours into the bone can lead to irreparable damage to the tissue. Examples include multiple myeloma (Tian et al, 2003) and some forms of prostate cancer (Hall et al, 2005). Damage of the bone by malignancy can increase the severity of the disease by providing a permissive microenvironment for tumour growth and metastatic events. In multiple myeloma, Dkk-1 is readily detectable in the blood of individuals in the later stages of the disease who have characteristic osteolytic bone lesions (Tian et al, 2003).

maybe this is interesting

Prague - Thanks for looking into that. I hoped that lithium might block DKK-1, but it can possibly protect Wnt inhbition from DKK-1 by inhibiting GSK-3beta. For example my lithium topical cuts out the sebum and also the Malassezia yeasts, but it may be limited on all the destructive forces of DKK-1. I'm just not sure. Interestingly, since DKK-1 has a negative effect on neurodegenerative disorders, lithium does the opposite by protecting them.

One thing that I found recently that was a bit of a surprise was that E2 (Estradiol) inhibits DKK-1
by suppressing the activation of JNK/c-Jun

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2639789

Another surprise was how progesterone upregulates DKK-1, at least in the endometrium.

http://jcem.endojournals.org/cgi/content/full/91/4/1453

DKK-1 is protective in some tissue (against colon cancer for instance) but in other tissue destructive. Even though Vitamin D in some areas activates DKK-1 action (probably protective under certain conditions), I know that insufficient vitamin D can cause multiple myeloma, so I wonder how it interacts there. Hopefully well figure this out eventually..