Cardiovascular disease (CVD) is an umbrella term for all the diseases of the heart and circulation including angina, congenital heart disease, coronary heart disease, heart attack and stroke. The World Health Organization (WHO) states that 17.9 million people die each year of cardiovascular diseases and this is set to rise to 26 million by 2030; according to WHO 80% of premature heart attacks and strokes are preventable. We know that the majority of CVD is due to dietary and lifestyle factors, many of which are modifiable and associated with obesity, stress and sedentary lifestyles.
For a long time, nutritional therapists have utilised phytonutrients such as resveratrol, lycopene and astaxanthin for their therapeutic benefits for the cardiovascular system. Their main function is often considered to be their antioxidant and anti-inflammatory properties. Although these properties are extremely important and useful, these phytonutrients are more sophisticated than merely mopping up excess free radicals. In this week’s blog, we shall explore the mechanisms by which these nutrients are considered to be protective for cardiovascular health.
Drivers of cardiovascular disease
There has been conflicting research in the past over the direct causes of cardiovascular disease leading to the demonisation of saturated fat, particularly in the 1970s. This led to an enormous increase in low fat diets in the 80s and 90s, which are still popular today; however the incidence of cardiovascular disease has continued to increase. The idea of saturated fat directly increasing atherosclerosis and fatty deposits within the vascular wall is too simplistic, there are many mechanisms which become dysfunctional and lead to the progression of CV conditions. Drivers of CVD include inflammation, oxidative stress, calcium dysregulation, endothelial dysfunction, mitochondrial dysfunction, insulin resistance and stress (high cortisol).1 Therefore prevention needs to be all encompassing and diet and lifestyle are central to this.
Phytonutrients and modulation of gene expression
Many phytonutrients can modulate transcription factors (molecules which are able to switch on or off certain genes) by affecting them directly or enzymes which regulate them; thus they can have an effect on gene expression. Some of the genes they interact with possess longevity properties and are protective against age-related conditions such as cardiovascular disease. Before discussing phytonutrients, it is useful to consider the functions of some enzymes and transcription factors which have CV protective properties.
Sirtuins are a family of seven enzymes, all of which possess a domain which can bind to nicotinamide adenine dinucleotide (NAD+ is an essential electron acceptor used in energy production). Thus they play an essential role in mitochondrial function, and also are involved in chromatin and histone production within the nucleus and as such are protective for DNA. They are additionally involved in a plethora of metabolic and homeostatic processes, including gluconeogenesis, fatty acid oxidation, oxidative phosphorylation, urea cycle, and endothelium homeostasis. Among the sirtuins, SIRT1 and SIRT6 (found mainly in the nucleus) are the best characterised for their protective roles against inflammation, vascular ageing, heart disease, and atherosclerotic plaque development. Whereas SIRT 2,3,4,5 and 7 are situated in the mitochondrial and cytosol and tend to be more involved in supporting energy production.2
PGC-1a (PPARγ Coactivator-1α)
PGC-1α transcriptional coactivators have recently emerged as powerful regulators of mitochondrial biology in the heart, they regulate gene expression from both nuclear and mitochondrial genomes. Research has demonstrated that PGC-1α is involved in many mechanisms associated with cardiovascular health, and is highly expressed in healthy cardiac cells. They have been shown to support mitochondrial function by upregulating key enzymes involved in the Kreb’s cycle, and increasing oxidation of fatty acids by beta-oxidation (therefore stimulating the use of fat for energy). They have also been associated with: blood vessel recruitment for transport of oxygen and nutrients and protection against reactive oxygen species (ROS) generated by the respiratory chain. Some, but not all, research has shown decreased expression of PGC-1α in failing human hearts.3,4
FOXO (Forkhead Box O)
The FOXO family is a group of transcription factors associated with longevity and protection against age-related conditions, which includes cardiovascular disease. They play many roles in supporting health and wellbeing and people with certain FOXO genes have been known to live longer. FOXO have been shown to stimulate autophagy (natural, regulated disassembly of a cell in order to remove a dysfunctioning cell and recycle components) in response to starvation. Defects in autophagy are associated with accelerated ageing and age-related disorders. Although there are many benefits of FOXO, the ones that are most specific to CVD are those that also increase the antioxidant capacity of cells and studies have shown that inactivating FOXO increases reactive oxygen species.5
AMPK (AMP-activated protein kinase)
AMPK (which regulates transcription factors via phosphorylation) activation is designed to halt energy consuming (anabolic) pathways and to promote energy conserving (catabolic) cellular pathways and has therefore often been dubbed the “metabolic master switch”. AMPK also plays a critical physiological role in the cardiovascular system mainly by activating antioxidant pathways as it promotes cardiovascular homeostasis by ensuring an optimum redox balance (equilibrium between free radical production and elimination) of the heart and vascular tissues. Dysfunctional AMPK is thought to underlie several cardiovascular pathologies.6
Like the others, AMPK has benefits to cardiovascular function as it:
- Improves nitric oxide (NO) bioavailability – NO diffuses to the surrounding tissue and exerts its multiple physiological effects which include vascular smooth muscle relaxation and proliferation, and inhibiting leukocyte adhesion and migration, platelet adhesion and aggregation and expression of adhesion molecules
- Enhances free fatty acid oxidation
- Possesses anti-inflammatory properties by blocking the NFκB signalling system
- Improves endothelial function
- Promotes the translocation of the glucose transporter 4 (GLUT-4) to the plasma membrane in the cardiomyocyte thus increasing the uptake of glucose to serve as the primary energy substrate7
Although it is very interesting to know about the function of these transcription factors and hence genes, it is only useful therapeutically if we know how they can be upregulated.
While the medical community is working hard on, and having success with, gene therapies, nutritional interventions have been shown to have an effect on these molecules from a therapeutic perspective. Although some of it is down to the luck of the genes you carry, it is the environment (such as diet and lifestyle) that the genes are exposed to that determines whether they are switched on or not (or off or not!). This is where phytonutrients come in…
This is probably the best studied phytonutrient in relation to cardiovascular health, likely due to the French Paradox, a concept formulated in the 1980s as a result of the observation that the French confounded the hypothesis that diets rich in saturated fats cause cardiovascular disease; the French, whose diet is very high in saturated fat, had a low incidence of heart disease. This was thought to be due to their consumption of red wine, a rich source of resveratrol. Whilst resveratrol has been shown to have protective properties for CVD, it is unlikely to be the sole contributor to the French Paradox. Indeed the French consume saturated fat from meat and butter, however they did not consume foods which are heavily processed and high in trans-fat, omega 6 oils, refined grains and sugar as well as (at that time) having a different lifestyle and approach to eating and drinking, all of which contribute to protection for health. Even so, evidence continues to grow for the therapeutic benefits of resveratrol. Research shows that it:4,8,9
- Activates AMPK and SIRTs (most research on SIRT1)
- Increases mitochondria capacity and fatty acid oxidation
- Reduces pro-inflammatory cytokines (TNFα and monocyte chemoattractant protein 1)
- Increases plasma antioxidant capacity and reduces reactive oxygen species
- Improves insulin sensitivity
- Improves endothelial function
- One study showed 70mg per day of resveratrol significantly increased flow mediated dilation (FMD) of the brachial artery, this is a biomarker of endothelial function and cardiovascular health
It has therefore been surmised that resveratrol is protective against and may reduce cardiovascular disease risk.
Lycopene is an antioxidant found in red fruits and vegetables, particularly tomatoes, and its bioavailability is improved by cooking or heating, therefore it is especially high in products such as tomato puree and sauces. Lycopene is lipid soluble, therefore, eating cooked tomatoes with some olive oil will also increase bioavailability. Evidence of the effects of tomato products and lycopene supplementation on CV risk factors supports the view that increasing the intake of these has positive effects on blood lipids, blood pressure and endothelial function. In preliminary studies lycopene has been also shown to upregulate AMPK expression.10,11
Astaxanthin is an antioxidant found in marine fish and shellfish, it gives krill their pink colour. Most of the benefits of astaxanthin relate to neuroprotection and there is a lot of research which supports its therapeutic use for cognitive health. However, research has also shown that astaxanthin demonstrates properties which are protective for cardiovascular health. Astaxanthin exhibits antioxidant properties which protect against homocysteine induced endothelial dysfunction (homocysteine is an independent risk factor which contributes to the occurrence and development of human cardiovascular diseases. Induction of oxidative stress and apoptosis is considered the major mechanism in homocysteine induced cardiotoxicity).12
Astaxanthin has demonstrated cardiovascular protective effects by:
- Exerting powerful antioxidant activities by quenching singlet oxygen and scavenging free radicals
- Inhibiting low-density lipoprotein (LDL) oxidation and increasing high-density lipoprotein (HDL)-cholesterol and adiponectin levels in clinical studies
- Exerting preventive actions against atherosclerotic cardiovascular disease (CVD) via its potential to improve inflammation and glucose metabolism
- Significantly reducing the production of pro-inflammatory cytokines (TNF-α and IL-6) in LPS-stimulated neutrophils
- Demonstrating ability to upregulate SIRT
In summary, it can be seen that phytonutrients possess properties which have the ability to affect gene expression as well as many other such as antioxidant and anti-inflammatory capabilities, mitochondrial support and improvements to glucose metabolism.
Similar effects to those seen as a result of the consumption of phytonutrients can be achieved through long-term caloric restriction. Caloric restriction is specifically defined as a reduction in energy intake well below the amount of calories that would be consumed, research shows it is best to reduce calorie intake by 25 – 50% but care needs to be taken that this reduced intake does not result in malnutrition.
The benefits of caloric restriction to cardiovascular health are:8,14
- Upregulation of SIRT, PGC-1a, AMPK and FOXO
- Improved mitochondrial function
- Reduced oxidative stress
- Increased nitric oxide production
- Improved insulin sensitivity
- Reduced inflammation
- Blood pressure reduction
- Attenuation of left-ventricular hypertrophy
- Resistance to myocardial ischemic injury
- Heart failure prevention.
Of course, long-term severe CR is not practical, feasible or sustainable for most people and can come with undesirable side effects such as extreme leanness, reduced bone density, sensitivity to cold, risk of malnutrition and other unpleasant effects. Therefore, the aim of CR research is to understand the mechanisms and how similar benefits might be achieved with fewer restrictions. Areas being researched include intermittent fasting, protein restriction and the use of selected nutrients – referred to as caloric restriction mimetics – such as resveratrol, nicotinamide riboside or nicotinamide adenine dinucleotide (NAD).
For example, nicotinamide riboside (a form of vitamin B3 that functions as a precursor to NAD) has shown similar benefits to caloric restriction in animal studies. Last year, a human clinical trial was published that showed improvements to blood pressure and arterial stiffness after 6 weeks supplementation. Larger and longer-term trials are needed. NAD is a rate limiting co-substrate for the family of sirtuin enzymes – increasing levels of the co-substrate NAD increases the activity of these enzymes; and oral supplementation with nicotinamide riboside has been shown to increase levels of NAD.15
Other relevant blogs
- Cardiovascular disease (CVD) risk is increased by many factors including oxidative stress, inflammation, poor blood sugar regulation and mitochondrial dysfunction (mitochondria are the energy power-houses of cells).
- Factors that are protective for CVD possess antioxidant, anti-inflammatory, mitochondrial supporting and blood sugar regulating properties. Some specific phytonutrients (found in vegetables, fruits, nuts, seeds and pink fish/krill) protect against CVD by directly having these properties.
- Phytonutrients have also been shown to increase the body’s production of other molecules which are protective. This is because certain phytonutrients can switch on genes that have anti-inflammatory and anti-oxidant effects; in addition they can regulate genes involved in energy production, glucose use and even genes related to increased longevity.
- Resveratrol is a phytonutrient found in red fruits, particularly grapes and therefore also red wine. It has many properties which protect the cardiovascular system, including effects on anti-ageing and longevity genes. Therefore demonstrating additional cardio protective effects by upregulating the body’s own protective processes.
- Lycopene found in high amounts in tomatoes (the bioavailability of which is increased by heating) and astaxanthin (a phytonutrient with red pigment found mainly in marine algae, we consume it in pink fish and shellfish) are protective due to their antioxidant properties but also have independent benefits to cardiovascular health, again via increasing anti-ageing and longevity genes.
- Caloric restriction (long-term reduction of calories by 25-50% without malnutrition) has similar effects to these phytonutrients, although this level of calorie reduction is not practical or desirable for most people and can result in unpleasant side effects and risks. Therefore, the aim of CR research is to understand the mechanisms and how similar benefits might be achieved with fewer restrictions. Areas being researched include intermittent fasting, protein restriction and the use of selected nutrients – referred to as caloric restriction mimetics – such as resveratrol, nicotinamide riboside or nicotinamide adenine dinucleotide (NAD).
- Nicotinamide Riboside (a form of vitamin B3) has been shown to mimic the effects of caloric restriction and therefore has the potential to be protective for CVD.
If you have any questions regarding the topics that have been raised, or any other health matters please do contact me (Helen) by phone or email at any time.
[email protected], 01684 310099
Helen Drake and the Cytoplan Editorial Team
Relevant Cytoplan Products
Cell-Active Glutathione – contains Liposomal glutathione, alpha lipoic acid, L-carnitine, rosemary, gingko biloba and resveratrol
Phytoshield – Phytonutrient and antioxidant complex containing flavonoids and carotenoids including lycopene
Krill Oil – Omega-3 supplement containing naturally occurring astaxanthin
Krill, K2 and CoQ10 – Omega-3 supplement containing naturally occurring astaxanthin with additional CoQ10, vitamin D3 and K2 and the phytonutrients resveratrol and lycopene
Nicotinamide Riboside – A unique member of the vitamin B3 family. The body converts NR into Nicotinamide Adenine Dinucleotide (NAD+) which is an essential molecule found in every living cell.
- Bland J et al. Textbook of Functional Medicine.; 2008.
- Hubbard BP, Sinclair DA. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol Sci. 2014;35(3):146-154.
- Rowe GC, Jiang A, Arany Z. PGC-1 coactivators in cardiac development and disease. Circ Res. 2010;107(7):825-838.
- Gambini J, Inglés M, Olaso G, et al. Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans. Oxid Med Cell Longev. 2015;2015:837042.
- Martins R, Lithgow GJ, Link W. Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell. 2016;15(2):196-207.
- Daskalopoulos EP, Dufeys C, Beauloye C, Bertrand L, Horman S. AMPK in Cardiovascular Diseases. In: Experientia Supplementum (2012). Vol 107. ; 2016:179-201.
- Shirwany NA, Zou M-H. AMPK in cardiovascular health and disease. Acta Pharmacol Sin. 2010;31(9):1075-1084.
- Dolinsky VW, Dyck JRB. Calorie restriction and resveratrol in cardiovascular health and disease. Biochim Biophys Acta – Mol Basis Dis. 2011;1812(11):1477-1489.
- Ramírez-Garza S, Laveriano-Santos E, Marhuenda-Muñoz M, et al. Health Effects of Resveratrol: Results from Human Intervention Trials. Nutrients. 2018;10(12):1892.
- Song B, Liu K, Gao Y, et al. Lycopene and risk of cardiovascular diseases: A meta-analysis of observational studies. Mol Nutr Food Res. 2017;61(9):1601009.
- Lin J, Xia J, Zhao H-S, et al. Lycopene triggers Nrf2-AMPK crosstalk to alleviate atrazine-induced nephrotoxicity in mice. J Agric Food Chem. October 2018:acs.jafc.8b04341.
- Fan C-D, Sun J-Y, Fu X-T, et al. Astaxanthin Attenuates Homocysteine-Induced Cardiotoxicity in Vitro and in Vivo by Inhibiting Mitochondrial Dysfunction and Oxidative Damage. Front Physiol. 2017;8:1041.
- Kishimoto Y, Yoshida H, Kondo K. Potential Anti-Atherosclerotic Properties of Astaxanthin. Mar Drugs. 2016;14(2).
- Bales CW, Kraus WE. Caloric restriction: implications for human cardiometabolic health. J Cardiopulm Rehabil Prev. 2013;33(4):201-208.
- Belenky, P. et al. (2007) ‘Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/MeuI pathway to NAD+’. Cell, 4, 129, 3, 473-84