We confirmed that both cytological apoptotic alterations and fragmentation of nuclear DNA occur in the interdigital tissue and presumptive joint areas of fetal mouse limbs, and they appear to play a significant role in the separation of digits as well as the formation of joint cavities.

Background-Carbon dioxide-rich water bathing has the effect of vasodilatation, whereas it remains undetermined whether this therapy exerts an angiogenic action associated with new vessel formation. Methods and Results-Unilateral hindlimb ischemia was induced by resecting the femoral arteries of C57BL/J mice.Lower limbs were immersed in CO 2 -enriched water (CO 2 concentration, 1000 to 1200 mg/L) or freshwater (control) at 37°C for 10 minutes once a day. Laser Doppler imaging revealed increased blood perfusion in ischemic limbs of CO 2 bathing (38% increase at day 28, PϽ0.001), whereas N G -nitro-L-arginine methyl ester treatment abolished this effect. Angiography or immunohistochemistry revealed that collateral vessel formation and capillary densities were increased (4.1-fold and 3.7-fold, PϽ0.001, respectively). Plasma vascular endothelial growth factor (VEGF) levels were elevated at day 14 (18%, PϽ0.05). VEGF mRNA levels, phosphorylation of NO synthase, and cGMP accumulation in the CO 2 -bathed hindlimb muscles were increased (2.7-fold, 2.4-fold, and 3.4-fold, respectively) but not in forelimb muscles. The number of circulating LinϪ/Flk-1ϩ/CD34Ϫ endothelial-lineage progenitor cells was markedly increased by CO 2 bathing (24-fold at day 14, PϽ0.001). The LinϪ/Flk-1ϩ/CD34Ϫ cells express other endothelial antigens (endoglin and VE-cadherin) and incorporated acetylated LDL. Conclusions-Our present study demonstrates that CO 2 bathing of ischemic hindlimb causes the induction of local VEGF synthesis, resulting in an NO-dependent neocapillary formation associated with mobilization of endothelial progenitor cells.

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Statins inactivate the RhoA pathway, resulting in over-expression of klotho mRNA, which may contribute to the novel pleiotropic effects of statins towards vascular protection.

SUMMARYWe examined the plasma levels of soluble Fas (sFas) or Fas ligand (sFas-L), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) in patients with idiopathic nonobstructive (HNCM) and dilated-phase (DHCM) hypertrophic cardiomyopathy.Patients with idiopathic hypertrophic cardiomyopathy (HCM) may deteriorate to DHCM and the pathogenesis is unknown.The levels of these plasma cytokines were measured by ELISA and echocardiography was performed in 38 HNCM and 11 DHCM patients, and 10 normal subjects. The followup period was three years.In HNCM, TNF-α (43.3 ± 45.2 versus 16.9 ± 4.3 pg/mL) and IL-6 (65.1 ± 86.4 versus 4.0 ± 2.1 pg/mL) were slightly higher compared to normal subjects and sFas (3.7 ± 1.2 versus 2.1 ± 0.7 ng/mL) increased significantly. sFas (3.9 ± 1.8), TNF-α (79.3 ± 72.4), and IL-6 (234.1 ± 135.2) in DHCM were significantly increased and only IL-6 was significantly different from HNCM. sFas-L (0.18 ± 0.08 versus 0.25 ± 0.05 ng/mL) in HNCM was significantly decreased, and the decrease was marked in DHCM (0.05 ± 0.02). In HNCM, TNF-α was negatively correlated with fractional shortening (r = -0.432, P = 0.0062) or positively with IL-6 (r = 0.665, P < 0.0001), while sFas-L was negatively correlated with IL-6 (r = -0.580, P < 0.0001). DHCM with high sFas had significantly higher cumulative incidences of worsening heart failure.The Fas/Fas-L system and proinflammatory cytokines may play an important role in the status of HCM and its progression to DHCM. (Int Heart J 2005; 46: 231-244)