Vascular SMC proliferation is a crucial event in occlusive cardiovascular diseases. PPARα is a nuclear receptor controlling lipid metabolism and inflammation, but its role in the regulation of SMC growth remains to be established. Here, we show that PPARα controls SMC cell-cycle progression at the G 1 /S transition by targeting the cyclin-dependent kinase inhibitor and tumor suppressor p16 INK4a (p16), resulting in an inhibition of retinoblastoma protein phosphorylation. PPARα activates p16 gene transcription by both binding to a canonical PPAR-response element and interacting with the transcription factor Sp1 at specific proximal Sp1-binding sites of the p16 promoter. In a carotid arterial-injury mouse model, p16 deficiency results in an enhanced SMC proliferation underlying intimal hyperplasia. Moreover, PPARα activation inhibits SMC growth in vivo, and this effect requires p16 expression. These results identify an unexpected role for p16 in SMC cell-cycle control and demonstrate that PPARα inhibits SMC proliferation through p16. Thus, the PPARα/p16 pathway may be a potential pharmacological target for the prevention of cardiovascular occlusive complications of atherosclerosis.

The ACE I/D polymorphism influences the level of late luminal loss after coronary stent implantation. These results suggest that the renin-angiotensin system may be implicated in the pathogenesis of restenosis after coronary stenting.

The AT1 receptor gene polymorphism is associated with coronary vasomotion in humans.

This observation suggests that variability of the PRNP locus may be associated with cognitive performance in the elderly. This result, if confirmed, offers potential clues for the role of PRNP in the human brain.

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A gene polymorphism of the angiotensin II (AII) type 1 receptor has been described previously (A to C transversion at position 1166). Besides the epidemiological studies needed to determine a possible relationship between the polymorphism and some cardiovascular diseases, no study has been conducted to determine the impact of the polymorphism on vascular functions. At subthreshold concentrations, within the physiological range, AII potentiates α-adrenergic-dependent vascular tone. We investigated phenylephrine-induced tone and its amplification by AII (10 pmol/l) in human internal mammary artery rings mounted in organ baths. We performed concentration-response curves to phenylephrine (0.1–100 µmol/l) before and after pretreatment with AII (10 pmol/l). Patients had the genotype AA (n = 20) or the A to C transversion (AC/CC, n = 30). Contractions to phenylephrine (0.1–100 µmol/l) were significantly higher in rings from AC/CC than from AA patients (maximum response: 1.47±0.07 vs. 1.22±0.06 mN/mg, p < 0.001). AII (10 pmol/l) induced a significant potentiation of phenylephrine-induced contraction (e.g. 58.9% increase in tone with 1 µmol/l phenylephrine, p < 0.001) which was significantly lower in the AC/CC than in the AA group (46±9 vs. 66±7% with 1 µmol/l phenylephrine, p < 0.01). Contractions to AII (1 or 100 nmol/l) were not significantly affected by the genotype. Although the study was performed in arteries from patients with a coronary artery disease, these changes in vascular reactivity might be of interest in the understanding of the relationship between a possible higher probability of cardiovascular disorder and the genetic polymorphism of the AII type 1 receptor.

Objective-To analyse the potential association of the angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (ATIR) gene polymorphisms on left ventricular function and mass in patients with normal coronary arteries. Design-Consecutive sample. Setting-University hospital. Subjects-141 consecutive white patients referred for coronary angiography and with angiographically normal coronary arteries. Patients with valvar diseases, cardiomyopathies, or a history of myocardial infarction were excluded. Main outcome measures-Left ventricular variables were measured for all patients. The ACE and ATIR genotypes were determined with a polymerase chain reaction based protocol using DNA prepared from white blood cells. A general linear model was used to compare data according to the ACE and to the ATlR genotypes. Results-A strong association was observed between left ventricular mass and systemic hypertension (mean (SD) hypertension: 114 (31) g/m2; no hypertension 98 (23) glm2; P < 0.003). However, no influence of ACE and ATIR polymorphisms on left ventricular mass was found, regardless of systemic hypertension. The subjects homozygous for the ATIR CC mutation had a significantly lower ejection fraction than those with allele A (AC+AA) (mean (SD) 62(12)% and 68(10)%, respectively, P < 0.05). No synergistic interaction of ACE and ATlR gene polymorphisms on left ventricular function and mass was found. Conclusions-These data do not support an association of the ACE and ATIR genotypes on left ventricular hypertrophy in white patients with normal coronary arteries. (Heart 1997;77:502-505)