L-Arginine and Genetic Susceptibility to Cardiovascular Diseases

The occurrence and progression of cardiovascular diseases (CVDs) result from the combined effects of genetic and environmental factors. Genetic susceptibility determines an individual’s predisposition to diseases, while environmental factors (e.g., diet, lifestyle) regulate genetic-related pathways and influence disease risk. As a semi-essential amino acid in the human body, L-arginine (L-Arg) serves as the sole substrate for endogenous nitric oxide (NO) synthesis and participates in the biosynthesis of bioactive substances such as polyamines and proline. Its metabolic pathways are closely associated with the core physiological functions of the cardiovascular system. More importantly, the metabolic efficiency and physiological effects of L-arginine are directly linked to the polymorphisms of multiple candidate genes for cardiovascular diseases, thereby affecting an individual’s genetic susceptibility to such diseases. This article systematically analyzes the association between key gene polymorphisms in the L-arginine metabolic pathway and genetic susceptibility to cardiovascular diseases, as well as the intervention value of L-arginine in genetically susceptible populations.

I. Core Genes in the L-Arginine Metabolic Pathway and Genetic Susceptibility to Cardiovascular Diseases

The biological effects of L-arginine mainly depend on two pathways: the nitric oxide synthase (NOS)-NO pathway and the arginine decarboxylase (ADC)-polyamine pathway. Key genes in these two pathways exhibit single nucleotide polymorphisms (SNPs). These gene polymorphisms alter enzyme activity, substrate affinity, or protein expression levels, affecting the metabolic efficiency of L-arginine and further regulating an individual’s genetic susceptibility to cardiovascular diseases.

1. Polymorphisms of Genes in the Nitric Oxide Synthase (NOS) Family

The NOS family includes endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and neuronal nitric oxide synthase (nNOS). Among them, eNOS gene polymorphisms show the closest association with genetic susceptibility to cardiovascular diseases.

eNOS gene rs1799983 polymorphism (Glu298Asp): A G→T mutation at this locus results in the substitution of glutamic acid with aspartic acid at position 298 of the encoded protein, which reduces the stability and activity of eNOS and decreases NO production. Individuals carrying this mutant allele (T allele) exhibit impaired vascular endothelial diastolic function and enhanced vascular smooth muscle cell proliferation, significantly increasing their genetic susceptibility to hypertension, coronary atherosclerotic heart disease (CHD), and heart failure. Clinical studies have shown that individuals with the rs1799983 TT genotype have a 2–3 times higher risk of developing CHD compared to those with the GG genotype, and they are more prone to vascular endothelial dysfunction.

eNOS gene rs2070744 polymorphism: This locus is located in the promoter region of the eNOS gene. A T→C mutation reduces gene transcription efficiency and decreases eNOS protein expression, leading to insufficient NO synthesis, elevated pulmonary vascular resistance, and a significantly increased risk of pulmonary arterial hypertension. Meanwhile, the vascular endothelium becomes more sensitive to oxidative stress, accelerating the formation of atherosclerotic plaques.

iNOS gene polymorphisms: iNOS is highly expressed under inflammatory conditions. Its gene polymorphisms (e.g., rs2297518) can affect enzyme activity. Individuals carrying the mutant allele exhibit excessively high iNOS activity under inflammatory states, resulting in excessive NO production. Excess NO reacts with superoxide anions to form peroxynitrite, exacerbating vascular endothelial damage and increasing the risk of acute coronary syndrome.

2. Polymorphisms of Arginase (Arg) Genes

Arginase is a key rate-limiting enzyme in L-arginine metabolism, which hydrolyzes L-arginine into ornithine and urea, competing with the NOS family for the substrate L-arginine. Its gene polymorphisms affect NO synthesis efficiency by altering enzyme activity.

Arginase 1 (Arg1) gene polymorphisms: Arg1 is mainly expressed in the liver and vascular endothelial cells. The rs2070633 polymorphism of the Arg1 gene can enhance enzyme catalytic activity, accelerate L-arginine degradation, cause insufficient NOS substrate supply, and reduce NO production. Individuals carrying this mutant allele show decreased vascular diastolic function, elevated peripheral vascular resistance, and significantly increased genetic susceptibility to hypertension. Additionally, the instability of atherosclerotic plaques is enhanced, making them more prone to plaque rupture.

Arginase 2 (Arg2) gene polymorphisms: Arg2 is mainly expressed in cardiomyocytes and vascular smooth muscle cells. The rs1801552 polymorphism of the Arg2 gene can enhance enzyme activity, consume L-arginine in cardiomyocytes, reduce NO production, impair cardiomyocyte diastolic function, and increase the risk of hypertrophic cardiomyopathy and heart failure.

3. Polymorphisms of Other Related Genes

Dimethylarginine dimethylaminohydrolase (DDAH) gene polymorphisms: DDAH can degrade asymmetric dimethylarginine (ADMA), an endogenous NOS inhibitor. Its gene polymorphisms (e.g., rs805303) can reduce enzyme activity, leading to ADMA accumulation and inhibition of NOS activity. This disrupts L-arginine metabolism, and individuals carrying the mutant allele have elevated ADMA levels, with a significantly increased risk of CHD and stroke.

Angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism: Individuals with the ACE gene DD genotype exhibit increased ACE activity, elevated angiotensin Ⅱ production, and subsequent vascular contraction and remodeling. Studies have found that there is a gene-gene interaction between the DD genotype and the eNOS gene rs1799983 TT genotype. Individuals carrying both mutant genotypes have a much higher risk of developing hypertension complicated with CHD compared to those with a single gene mutation or wild-type genotype. However, L-arginine supplementation can partially reverse this risk by increasing substrate concentration.

II. Impact of Genetic Susceptibility on the Intervention Efficacy of L-Arginine

The intervention efficacy of L-arginine on cardiovascular diseases varies significantly among individuals, which is mainly determined by the aforementioned gene polymorphisms. Individuals with different genotypes exhibit distinct L-arginine metabolic efficiency and NO production capacity, leading to differentiated intervention effects.

1. Impact of eNOS Gene Polymorphisms on L-Arginine Intervention Efficacy

Individuals carrying the eNOS gene rs1799983 TT genotype have reduced eNOS activity. Exogenous L-arginine supplementation can partially restore NOS catalytic efficiency, increase NO production, and improve vascular endothelial diastolic function by increasing substrate concentration. Clinical studies have shown that after 8 weeks of oral L-arginine supplementation (3 g per day), the flow-mediated dilation (FMD) of the brachial artery in such populations is significantly improved, and the risk of CHD is reduced. In contrast, wild-type individuals carrying the GG genotype have normal endogenous eNOS activity, and L-arginine supplementation exerts no significant improvement effect on vascular endothelial function.

On the contrary, individuals carrying the eNOS gene rs2070744 CC genotype have low gene transcription efficiency and insufficient eNOS protein expression. The intervention efficacy of L-arginine supplementation alone is limited. It is necessary to combine L-arginine with NOS activators (e.g., folic acid) to effectively improve vascular function through the dual mechanisms of enhancing eNOS activity and increasing substrate concentration.

2. Impact of Arginase Gene Polymorphisms on L-Arginine Intervention Efficacy

Individuals carrying the Arg1 gene rs2070633 mutant allele have excessively high arginase activity. Conventional doses of L-arginine supplementation are rapidly degraded, making it difficult to effectively increase NO levels. Such populations require higher doses of L-arginine (5–10 g per day) or combination with arginase inhibitors (e.g., Nω-hydroxy-L-arginine) to inhibit arginase activity, reduce L-arginine degradation, and significantly increase NO production, thereby lowering peripheral vascular resistance.

3. Impact of Gene-Gene Interactions on L-Arginine Intervention Efficacy

Individuals carrying both the ACE gene DD genotype and the eNOS gene rs1799983 TT genotype exhibit significant gene-gene interactions, with superimposed risks of vascular contraction and endothelial dysfunction. Studies have shown that supplementation with L-arginine (5 g per day) combined with angiotensin receptor blockers (ARBs) in such populations can synergistically improve vascular diastolic function and reduce the risk of hypertension and CHD. In contrast, the intervention efficacy of single-drug or single-nutrient therapy is far lower than that of the combined regimen.

III. Cardiovascular Protection Strategies of L-Arginine for Genetically Susceptible Populations

For populations genetically susceptible to cardiovascular diseases, L-arginine intervention should follow a gene-guided individualized strategy, and precise supplementation regimens should be formulated based on gene polymorphism characteristics to maximize its cardiovascular protective effects.

1. L-Arginine Dosage Adjustment Based on Genotyping

eNOS gene hypofunctional type (e.g., rs1799983 TT genotype): Oral L-arginine supplementation at 3–5 g per day for 8–12 weeks is recommended, which can effectively increase NO levels and improve vascular endothelial function. For those complicated with hypertension, combination with folic acid (0.8 mg per day) is advisable. Folic acid can reduce homocysteine levels, enhance eNOS activity, and produce a synergistic effect with L-arginine.

Arginase hyperactive type (e.g., Arg1 rs2070633 mutant type): Oral L-arginine supplementation at 5–10 g per day or combination with low-dose arginase inhibitors is recommended to reduce L-arginine degradation and improve its bioavailability. Meanwhile, high-protein diets should be avoided to reduce endogenous L-arginine consumption.

Gene-gene interaction type (e.g., ACE DD + eNOS TT genotype): L-arginine (5 g per day) combined with ARBs (e.g., losartan) is recommended to reduce vascular resistance and delay vascular remodeling through the dual mechanisms of inhibiting angiotensin Ⅱ and increasing NO levels.

2. Combined Nutrient Intervention to Enhance Protective Effects in Genetically Susceptible Populations

L-arginine has synergistic effects with various nutrients, which can further enhance cardiovascular protection in genetically susceptible populations:

L-arginine + folic acid + vitamin B12: Folic acid and vitamin B12 can reduce homocysteine levels, which inhibits eNOS activity. Supplementation with these two vitamins can relieve the inhibition of eNOS, synergistically increase NO production with L-arginine, and is particularly suitable for populations with eNOS gene polymorphisms.

L-arginine + ω-3 polyunsaturated fatty acids: ω-3 polyunsaturated fatty acids can inhibit inflammatory responses and platelet aggregation. Combined use with L-arginine can synergistically improve the stability of atherosclerotic plaques, reduce the risk of acute coronary syndrome, and is suitable for populations with arginase gene polymorphisms.

3. Combined Lifestyle Intervention to Reduce Disease Risk in Genetically Susceptible Populations

The risk of cardiovascular diseases in genetically susceptible populations can be further reduced through lifestyle intervention, which exerts a synergistic effect with L-arginine supplementation:

Low-salt diet: High salt intake reduces eNOS activity and exacerbates vascular endothelial dysfunction. Genetically susceptible populations should control daily salt intake below 5 g to avoid weakening the intervention efficacy of L-arginine.

Regular exercise: Aerobic exercise can increase eNOS expression and activity, enhancing L-arginine metabolic efficiency. Genetically susceptible populations are advised to perform 150 minutes of moderate-intensity aerobic exercise per week, such as brisk walking and swimming.

Despite significant progress in research on the association between L-arginine and genetic susceptibility to cardiovascular diseases, many challenges remain:

Complexity of gene polymorphisms: Genetic susceptibility to cardiovascular diseases is determined by multiple gene loci. Studies on single loci cannot fully explain individual differences. Future research should conduct genome-wide association studies (GWAS) to analyze the impact of multi-gene interactions on L-arginine metabolism.

Clinical translation of individualized intervention: Currently, there is a lack of large-sample, long-term clinical research data to support gene-typing-based individualized L-arginine supplementation regimens. Further prospective cohort studies are needed to clarify the optimal intervention dosage and course of treatment for populations with different genotypes.

In-depth research on gene-environment interactions: Environmental factors such as diet, exercise, and stress can regulate the expression of genes in the L-arginine metabolic pathway through epigenetic modifications. Future research should further explore the mechanisms of gene-environment interactions to develop more precise comprehensive intervention strategies for genetically susceptible populations.