Negative association between lipoprotein associated phospholipase A2 activity and baroreflex sensitivity in subjects with high normal blood pressure and a positive family history of hypertension.

The relationship between baroreflex sensitivity (BRS) and inflammatory vascular biomarker Lipoprotein associated phospholipase A2 (Lp-PLA2) in subjects with high normal blood pressure (HNBP, prehypertensives) with a positive family history of hypertension (FHH+) and hypertension history free control subjects (FHH-) was evaluated. A total of 24 HNBP participants (age 39.5 ± 2.5 years, 18 male/ 6 female) were studied. 14 HNBP subjects FHH+ were compared to 10 HNBP participants FHH-, being of similar age and body mass index. BRS (ms/mmHg) was determined by the sequence and spectral methods (five-minute non-invasive beat-to-beat recording of blood pressure and RR interval, controlled breathing at a frequency of 0.33 Hz). Venous blood was analyzed for Lp-PLA2 biomarker of vascular inflammation and atherothrombotic activity. A significant negative correlation between spontaneous BRS obtained by both methods and systolic blood pressure (BP) was present (BRS spect r = -0.54, P<0.001, BRS seq r = -0.59, P<0.001). BRS obtained by sequence and spectral methods were reduced in HNBP FHH+ compared to the group of HNBP FHH- (P = 0.0317 BRS seq, P = 0.0395 BRS spect). Lp-PLA2 was significantly higher in HNBP FHH+ compared to FHH- controls (P<0.05). Lp-PLA2 was negatively correlated with BRS obtained by sequence method (r = -0.798, R2 = 0.636, P<0.001) in the HNBP FHH+ subjects. These findings demonstrate that reduced baroreflex sensitivity, as a marker of autonomic dysfunction, is associated with vascular inflammation, predominantly in otherwise healthy participants with a positive family history of hypertension who could predispose to increased risk of hypertension. We conclude that our transversal study suggests that a lowbaroreflex sensitivity could be an early sign of autonomic dysfunction even in the prehypertensive period, and to corroborate these findings, a longitudinal study is needed.

Survivin, a novel target of the Hedgehog/GLI signaling pathway in human tumor cells.

Survivin, an important antiapoptotic protein, is expressed in tumors, whereas in normal tissues the expression of this protein is extremely low, defining a role for survivin as a cancer gene. Survivin exhibits multifunctional activity in tumor cells. However, why survivin expression is sharply and invariably restricted to tumor tissue remains unclear. Here, we identified 11 putative consensus binding sites for GLI transcription factors in the survivin promoter and characterized the promoter activity. Inhibitors of the Hedgehog/GLI pathway, cyclopamine and GANT61, decreased the promoter activity in reporter assays. ΔNGLI2 (which lacks the repressor domain) was the most potent vector in activating the survivin promoter-reporter. Moreover, GANT61, a GLI1/2 inhibitor, repressed endogenous survivin protein and mRNA expression in most cells across a large panel of tumor cell lines. Chromatin immunoprecipitation showed GLI2 binding to the survivin promoter. The ectopic GLI2-evoked expression of endogenous survivin was observed in normal human fibroblasts. GANT61 decreased survivin level in nude mice tumors, mimicking the activity of GANT61 in cultured cells. The immunohistochemistry and double immunofluorescence of human tumors revealed a correlation between the tissue regions showing high GLI2 and survivin positivity. Thus, these results demonstrated that survivin is a classical transcriptional target of GLI2, a Hedgehog pathway signaling effector. This potentially reflects the high expression of survivin in human tumor cells. As the Hedgehog pathway is upregulated in virtually all types of cancer cells, these findings substantially contribute to the explanation of uniform survivin expression in tumors as a potential target for the development of a more effective treatment of cancers through the inhibition of GLI2 to restrain survivin activity.