Carlos Guijarro

Although cardiovascular disease is a major cause of morbidity and mortality after renal transplantation, its pathogenesis and treatment are poorly understood. We conducted separate analyses of risk factors for ischemic heart disease, cerebral, and peripheral vascular disease after 706 renal transplants, all of which functioned for at least 6 months. We used Cox proportional hazards analysis to examine the effects of multiple pretransplant and posttransplant risk factors and included time-dependent variables measured at 3, 6, and 12 months, and annually to last follow-up at 7.0 +/- 4.2 yr. The independent relative risk (RR) of diabetes was 3.25 for ischemic heart disease, 3.21 for cerebral vascular disease, and 28.18 peripheral vascular disease (P < 0.05). The RR of each acute rejection episode was 1.40 for ischemic heart disease and 1.24 for cerebral vascular disease. Among serum lipid levels, high-density lipoprotein cholesterol was the best predictor of ischemic heart disease (RR = 0.80 for each 10 mg/dL). Posttransplant ischemic heart disease was strongly predictive of cerebral (5.80) and peripheral vascular disease (5.22), whereas ischemic heart disease was predicted by posttransplant cerebral (8.25) and peripheral vascular disease (4.58). Other risk factors for vascular disease included age, gender, cigarette smoking, pretransplant splenectomy, and serum albumin. Hypertension and low-density lipoprotein cholesterol had no effect, perhaps because of aggressive pharmacologic treatment. Thus, the incidence of cardiovascular disease continues to be high after renal transplantation, and multiple risk factors suggest a number of possible strategies for more effective treatment and prevention.

Recent evidence suggests that apoptosis may be involved in the control of vascular smooth muscle cell (VSMC) number in atherosclerotic lesions. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to induce apoptosis in a variety of tumor cell lines. To evaluate whether these agents also induce apoptosis of VSMCs, cultured rat VSMCs were treated with increasing doses of atorvastatin in the presence of FBS as a survival factor. The presence of apoptosis was evaluated by morphological criteria, annexin V binding, and DNA fragmentation and quantified as the proportion of hypodiploid cells by flow cytometry. Atorvastatin induced apoptosis in a dose-dependent manner, an effect also seen with simvastatin and lovastatin, but not with the hydrophilic drug pravastatin. The proapoptotic effect of statins was seen only when the inhibition of acetate incorporation into sterols was >95% and was fully reversed by mevalonate, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate but not by isopentenyl adenosine, ubiquinone, or squalene, suggesting a role for prenylated proteins in the regulation of VSMC apoptosis. To further assess the role of protein prenylation, VSMCs were exposed to the prenyl transferase inhibitors perillic acid and manumycin A. Both agents induced VSMC apoptosis as evaluated by the above-mentioned criteria. Finally, VSMC treatment with lipophilic statins was associated with decreased prenylation of p21-Rho B, further supporting the role of protein prenylation inhibition in statin-induced VSMC apoptosis. The present data suggest that interference with protein prenylation by HMG-CoA reductase inhibitors or other agents may provide new strategies for the prevention of neointimal thickening.