Two genetic variants in the promoter region of the CCL5 gene are associated with the risk of acute coronary syndrome and with a lower plasma CCL5 concentration.

Acute coronary syndrome (ACS) is a multi-factorial condition with a strong inflammatory component, which is immune-mediated by chemokines. The CCL5 is a chemokine that has been suggested to be an important participant in the development of the atherosclerotic plaque. Therefore, in this work, we evaluated whether three polymorphisms located in the promoter region of the CCL5 gene [CCL5 -28 G/C (rs2280788), CCL5-109 G/A (rs1800825), and CCL5-403 G/A (rs2107538)] are significantly associated with the acute coronary syndrome (ACS), and plasma CCL5 levels. The determination of the gene polymorphisms was performed by 5'exonuclease TaqMan assays in 625 patients with ACS and 700 control individuals. Plasma CCL5 levels were evaluated by ELISA. Under co-dominant, dominant, and additive models, the G allele of the -109 G/A polymorphism was associated with a higher risk of ACS (OR = 1.27, pCCo-dom = 0.041, OR = 1.33, pCDom = 0.03, and OR = 1.33, pCAdd = 0.015, respectively). In the same way, under co-dominant and recessive models, the A allele of the -403 G/A polymorphism was associated with an increased risk of ACS (OR = 1.62, pCCo-dom = 0.042, and OR = 1.63, pCRes = 0.012, respectively). The CCL5-109 G allele carriers had a lower concentration of the CCL5 than subjects with the A allele. Also, carriers of CCL5-403 A allele showed a lower concentration of the CCL5 than individuals with the G allele. Our data suggest the association of the CCL5-109 G/A and CCL5-403 G/A polymorphisms with the risk of developing ACS and with a lower concentration of CCL5 in our population.

The c.*52 A/G and c.*773 A/G Genetic Variants in the UTR'3 of the LDLR Gene Are Associated with the Risk of Acute Coronary Syndrome and Lower Plasma HDL-Cholesterol Concentration.

Dyslipidemia has a substantial role in the development of acute coronary syndrome (ACS). Low-density lipoprotein receptor (LDLR) plays a critical role in plasma lipoprotein hemostasis, which is involved in the formation of atherosclerotic plaque. This study aimed to evaluate whether LDLR gene polymorphisms are significantly associated with ACS and the plasma lipids profile. Three LDLR gene polymorphisms located in the UTR'3 region (c.*52 A/G, c.*504 A/G, and c.* 773 A/G) were determined using TaqMan genotyping assays in a group of 618 ACS patients and 666 healthy controls. Plasma lipids profile concentrations were determined by enzymatic/colorimetric assays. Under co-dominant and recessive models, the c.*52 A allele of the c.*52 A/G polymorphism was associated with a higher risk of ACS (OR = 2.02, pCCo-dom = 0.033, and OR = 2.00, pCRes = 0.009, respectively). In the same way, under co-dominant and recessive models, the c.*773 G allele of the c.*773 A/G polymorphism was associated with a high risk of ACS (OR = 2.04, pCCo-dom = 0.027, and OR = 2.01, pCRes = 0.007, respectively). The "AAG" haplotype was associated with a high risk of ACS (OR = 1.22, pC = 0.016). The c.*52 AA genotype showed a lower HDL-C concentration than individuals with the GG genotype. In addition, carriers of c.*773 GG genotype carriers had a lower concentration of the high-density lipoprotein-cholesterol (HDL-C) than subjects with the AA genotype. Our data suggest the association of the LDLRc.*773 A/G and LDLR c.*52 A/G polymorphisms with both the risk of developing ACS and with a lower concentration of HDL-C in the study population.

SREBF1c and SREBF2 gene polymorphisms are associated with acute coronary syndrome and blood lipid levels in Mexican population.

AIM: It has recently been reported that the sterol regulatory element-binding transcription factors (SREBF-1c, and -2) contribute to the variation in the plasma lipids levels, which have an important role in the atherosclerotic plaque development. The aim of the present study was to evaluate whether the SREBF1c and SREBF2 gene single nucleotide polymorphisms (SNPs) are associated with plasma lipids levels and ACS susceptibility in a case-control association study. MATERIAL AND METHODS: A case-control study was carried out in 625 patients with ACS (82% men and 18% women, with a mean age of 57.97 ± 10.5 years) and 700 healthy controls (66% men and 34% women, with a mean age of 54.37 ± 7.65 years). The sample size was calculated for a statistical power of 80%. We genotyped three SREBF1c (rs2297508, rs11656665 and rs11868035) and three SREBF2 (rs2267439, rs2267443, and rs2228314) gene polymorphisms by 5' exonuclease TaqMan assays. The associations were evaluated by logistic regression under the co-dominant, dominant, recessive, over-dominant and additive inheritance models. The contribution of the genotypes on the plasma lipids levels was evaluated by Student's t-test. RESULTS: Under different models, the SREBF1c rs2297508 (OR = 1.50, pCRes = 0.03), SREBF1c rs11656665 (OR = 1.35, pCDom = 0.02 and OR = 1.26, pCAdd = 0.02) and SREBF2 rs2228314 (OR = 1.78, pCRes = 0.03, OR = 1.27, pCAdd = 0.04) SNPs were associated with higher risk of ACS. On the other hand, the SREBF1c rs11868035 SNP was associated with lower risk of ACS (OR = 0.49, pCCo-dom = 0.001, OR = 0.66, pCDom = 0.003, OR = 0.57, PRes = 0.003 and OR = 0.71, pCAdd = 0.001). There was a statistically significant association of both SREBF1c rs11656665 and rs11868035 polymorphisms with plasma triglyceride levels. CONCLUSIONS: In summary, our data suggest the association of the SREBF1c and SREBF2 SNPs with risk of developing ACS and with triglyceride levels in a Mexican population.

Age-, Gender-, and in Vivo Different Doses of Isoproterenol Modify in Vitro Aortic Vasoreactivity and Circulating VCAM-1.

Different human-like cardiomyopathies associated to ß-adrenergic stimulation are experimentally modeled in animals through variations in dose, route, and duration of administration of different cardiotoxic drugs. However, associated changes in the vasculature and their relation to systemic inflammation, and the influence of cardiovascular diseases risk factors (gender and age) upon them are seldom analyzed. Here we studied the effect of age and gender on the vasoreactivity of aortas from mice subjected to in vivo repeated ß-adrenergic stimulation with different doses of isoproterenol (ISO) in association with circulating inflammatory cytokines. Young (2 months) and old (18 months) male and female mice received 0 (control), 5, 40, 80 or 160 µg/g/d of ISO (7 days, s.c.). IL-1α, IL-4 and vascular cell adhesion molecule-1 (VCAM-1) were quantified in plasma. In vitro, norepinephrine-induced vasoconstriction and acetylcholine-induced relaxation were measured in aortas. No differences in contraction, relaxation, IL-1α, and IL-4 were found between control young males and females. Age decreased contraction in males and relaxation was lower in females and abolished in males. VCAM-1 was higher in young males than in females and increased in old mice. Vasoconstriction in ISO-treated mice results as a bell-shaped curve on contraction in young and old males, with lower values in the latter. In females, ISO-160 increased contraction in young females but decreased it in old females. Vasorelaxation was reduced in ISO-treated young males and females. ISO-80 and 160 reduced vasorelaxation in old females, and intermediate doses relaxed aortas from old males. VCAM-1 was higher in young and old males with ISO-80 and 160; while VCAM-1 was higher only with ISO-160 in old females. Our results demonstrate that repeated ß-adrenergic stimulation modifies vascular reactivity depending on gender, age, and dose. Females were less sensitive to alterations in vasoreactivity, and young females required a higher amount of the adrenergic stimuli than old females to show vascular alterations. Changes were independent of IL-1α and IL-4. VCAM-1 only changed in old females stimulated with ISO 160. Our results highlight the relevance of considering and comparing in the same study females and aged organisms to improve the accuracy of applications to clinical studies.

Functional and structural regeneration in the axolotl heart (Ambystoma mexicanum) after partial ventricular amputation.

"In the present study we evaluated the effect of partial ventricular amputation (PVA) in the heart of the adult urodele amphibian (Ambystoma mexicanum) in vivo on spontaneous heart contractile activity recorded in vitro in association to the structural recovery at one, five, 30 and 90 days after injury. One day after PVA, ventricular-tension (VT) (16 ± 3%), atrium-tension (AT) (46 ± 4%) and heart rate (HR) (58+10%) resulted lower in comparison to control hearts. On days five, 30 and 90 after damage, values achieved a 61 ± 5, 93 ± 3, and 98 ± 5% (VT), 60 ± 4, 96 ± 3 and 99 ± 5% (AT) and 74 ± 5, 84 ± 10 and 95 ± 10% (HR) of the control values, respectively. Associated to contractile activity recovery we corroborated a gradual tissue restoration by cardiomyocyte proliferation. Our results represent the first quantitative evidence about the recovery of heart of A. mexicanum restores its functional capacity concomitantly to the structural recovery of the myocardium by proliferation of cardiomyocytes after PVA. These properties make the heart of A. mexicanum a potential model to study the mechanisms underlying heart regeneration in adult vertebrates in vivo.

Functional and structural regeneration in the axolotl heart (Ambystoma mexicanum) after partial ventricular amputation / Regeneración funcional y estructural del corazón de axolotl (Ambystoma mexicanum) después de amputación parcial del ventrículo

In the present study we evaluated the effect of partial ventricular amputation (PVA) in the heart of the adult urodele amphibian (Ambystoma mexicanum) in vivo on spontaneous heart contractile activity recorded in vitro in association to the structural recovery at one, five, 30 and 90 days after injury. One day after PVA, ventricular-tension (VT) (16 ± 3%), atrium-tension (AT) (46 ± 4%) and heart rate (HR) (58 ± 10%) resulted lower in comparison to control hearts. On days five, 30 and 90 after damage, values achieved a 61 ± 5, 93 ± 3, and 98 ± 5% (VT), 60 ± 4, 96 ± 3 and 99 ± 5% (AT) and 74 ± 5, 84 ± 10 and 95 ± 10% (HR) of the control values, respectively. Associated to contractile activity recovery we corroborated a gradual tissue restoration by cardiomyocyte proliferation. Our results represent the first quantitative evidence about the recovery of heart contractile activity after PVA in an adult urodele amphibian, indicating that the heart of A. mexicanum restores its functional capacity concomitantly to the structural recovery of the myocardium by proliferation of cardiomyocytes after PVA. These properties make the heart of A. mexicanum a potential model to study the mechanisms underlying heart regeneration in adult vertebrates in vivo.

En el presente estudio evaluamos el efecto de la amputación parcial del ventrículo (APV) del corazón de un anfibio urodelo adulto (Ambystoma mexicanum) in vivo, sobre la actividad contráctil espontánea del corazón registrada in vitro, a diferentes tiempos después de APV, en asociación a su recuperación estructural. Un día después del daño, los valores de tensión ventricular (TV) (16 ± 3%), tensión auricular (TA) (46 + 4%) y frecuencia cardiaca (FC) (58 + 10%), resultaron ser menores respecto al control. En los días cinco, 30 y 90 después del daño, los valores alcanzaron 61 ± 5, 93 ± 3 y 98 ± 5% (TV), 60 ± 4, 96 ± 3 y 99 ± 5% (AT) y 74 ± 5, 84 ± 10 y 95 ± 10% (FC) de los valores control, respectivamente. Además de la recuperación de la actividad contráctil, corroboramos la recuperación estructural y gradual del tejido miocárdico por proliferación de cardiomiocitos. Nuestros resultados representan la primera evidencia cuantitativa de la recuperación de la actividad contráctil del corazón de un anfibio urodelo adulto después de APV; indicando que el corazón de A. mexicanum recupera su capacidad funcional concomitantemente con la recuperación estructural del miocardio por proliferación de cardiomiocitos. El corazón de A. mexicanum es un modelo potencial para el estudio de los mecanismos de la regeneración miocárdica de vertebrados adultos in vivo.