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Supravalvular aortic stenosis is an autosomal-dominant disease of elastin (Eln) insufficiency caused by loss-of-function mutations or gene deletion. Recently, we have modeled this disease in mice (Eln+/–) and found that Eln haploinsufficiency results in unexpected changes in cardiovascular hemodynamics and arterial wall structure. Eln+/– animals were found to be stably hypertensive from birth, with a mean arterial pressure 25–30 mmHg higher than their wild-type counterparts. The animals have only moderate cardiac hypertrophy and live a normal life span with no overt signs of degenerative vascular disease. Examination of arterial mechanical properties showed that the inner diameters of Eln+/– arteries were generally smaller than wild-type arteries at any given intravascular pressure. Because the Eln+/– mouse is hypertensive, however, the effective arterial working diameter is comparable to that of the normotensive wild-type animal. Physiological studies indicate a role for the renin-angiotensin system in maintaining the hypertensive state. The association of hypertension with elastin haploinsufficiency in humans and mice strongly suggests that elastin and other proteins of the elastic fiber should be considered as causal genes for essential hypertension

Background-Ca2ϩ release from the sarcoplasmic reticulum via the ryanodine receptor (RyR2) activates cardiac myocyte contraction. An important regulator of RyR2 function is FKBP12.6, which stabilizes RyR2 in the closed state during diastole. ␤-Adrenergic stimulation has been suggested to dissociate FKBP12.6 from RyR2, leading to diastolic sarcoplasmic reticulum Ca 2ϩ leakage and ventricular tachycardia (VT). We tested the hypothesis that FKBP12.6 overexpression in cardiac myocytes can reduce susceptibility to VT in stress conditions. Methods and Results-We developed a mouse model with conditional cardiac-specific overexpression of FKBP12.6.Transgenic mouse hearts showed a marked increase in FKBP12.6 binding to RyR2 compared with controls both at baseline and on isoproterenol stimulation (0.2 mg/kg IP). After pretreatment with isoproterenol, burst pacing induced VT in 10 of 23 control mice but in only 1 of 14 transgenic mice (PϽ0.05). In isolated transgenic myocytes, Ca 2ϩ spark frequency was reduced by 50% (PϽ0.01), a reduction that persisted under isoproterenol stimulation, whereas the sarcoplasmic reticulum Ca 2ϩ load remained unchanged. In parallel, peak I Ca,L density decreased by 15% (PϽ0.01), and the Ca 2ϩ transient peak amplitude decreased by 30% (PϽ0.001). A 33.5% prolongation of the caffeine-evoked Ca 2ϩ transient decay was associated with an 18% reduction in the Na ϩ -Ca 2ϩ exchanger protein level (PϽ0.05). Conclusions-Increased FKBP12.6 binding to RyR2 prevents triggered VT in normal hearts in stress conditions, probably by reducing diastolic sarcoplasmic reticulum Ca 2ϩ leak. This indicates that the FKBP12.6-RyR2 complex is an important candidate target for pharmacological prevention of VT.