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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.

Elastin, the main component of elastic fibers, is synthesized only in early life and provides the blood vessels with their elastic properties. With aging, elastin is progressively degraded, leading to arterial enlargement, stiffening, and dysfunction. Also, elastin is a key regulator of vascular smooth muscle cell proliferation and migration during development since heterozygous mutations in its gene (Eln) are responsible for a severe obstructive vascular disease, supravalvular aortic stenosis, isolated or associated to Williams syndrome. Here, we have studied whether early elastin synthesis could also influence the aging processes, by comparing the structure and function of ascending aorta from 6-and 24-month-old Eln+/− and Eln+/+ mice. Eln+/− animals have high blood pressure and arteries with smaller diameters and more rigid walls containing additional

Fibrillin-1, the major component of extracellular microfibrils that associate with insoluble elastin in elastic fibers, is mainly synthesized during development and postnatal growth and is believed to guide elastogenesis. Mutations in the fibrillin-1 gene cause Marfan syndrome, a multisystem disorder characterized by aortic aneurysms and dissections. The recent finding that early deficiency of elastin modifies vascular aging has raised the possibility that fibrillin-1 deficiency could also contribute to late-onset pathology of vascular remodeling. To address this question, we examined cardiovascular function in 3 week-old, 6 month-old, and 24 month-old mice that are heterozygous for a hypomorphic structural mutation of fibrillin-1 (Fbn1 +/mgΔ mice). Our results indicate that Fbn1 +/mgΔ mice, particularly those that are 24 month-old, are slightly more hypotensive than wild-type littermates. Additionally, aneurysm and aortic insufficiency were more frequently observed in aging Fbn1 +/mgΔ mice than in the wild-type counterparts. We also noted substantial fragmentation and decreased number of elastic lamellae in the aortic wall of Fbn1 +/mgΔ mice, which were correlated with an increase in aortic stiffness, a decrease in vasoreactivity, STATEMENT OF AUTHOR CONTRIBUTIONSMB and FG conceived and carried out experiments, and analysed data. HP and RF conceived experiments. PM, EB, BS, AJP, SB, QD and JMP carried out experiments. All authors were involved in writing the paper and had final approval of the submitted and published versions. NIH Public AccessAuthor Manuscript J Pathol. Author manuscript; available in PMC 2012 January 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript altered expressions of elastic fiber-related genes, including fibrillin-1 and elastin, and a decrease in the relative ratio between tissue elastin and collagen. Collectively, our findings suggest that the heterozygous mgΔ mutation accelerates some aspects of vascular aging and eventually lead to aortic manifestations resembling those of Marfan syndrome. Importantly, our data also indicate that vascular abnormalities in Fbn1 +/mgΔ mice are opposite to those induced by elastin haploinsufficiency during aging that affect blood pressure, vascular dimensions and number of elastic lamellae.

H aploinsufficiency of elastin in patients with WilliamsBeuren syndrome leads, in more than half of cases, to development of supravalvular aortic stenosis and hypertension.1 Moreover, Eln +/− mice, a model for supravalvular aortic stenosis disease, have a higher arterial pressure (∆25-30 mm Hg) than their wild-type counterparts.2 These cardiovascular features are clearly linked to the decreased elastin synthesis in the aorta during development. Thus, it would be of interest to find molecules able to enhance elastin synthesis to treat this condition.We previously showed that the Brown Norway (BN) rat, a normotensive inbred strain, presents the lowest content of elastin in the aorta compared with 6 other inbred rat strains. [3][4][5] We also demonstrated that, compared with the LOU rat, the elastin deficit in the thoracic aorta of the BN rat is partly caused by a decrease in the synthesis of tropoelastin (TE), the soluble precursor of elastin. However, elastin gene polymorphism accounts for only 3.9% of the elastin content variance in F2 BNxLOU rats.4 After a genome-wide search for quantitative trait loci influencing the aortic elastin content in an F2 population derived from BN and LOU rats, we identified on chromosomes 2 and 14, 3 quantitative trait loci specifically controlling elastin levels: Ael1, Ael2, and Ael3. 6 The polymorphic marker, D2Wox26, corresponding to the maximum logarithm of odds score value of Ael2, is situated within the gene encoding for the Na + /K + -ATPase α1 subunit. In addition, several other genes encoding for potassium channels are contained in Ael1 (Kcnmb2, Hcn1) and Ael2 (Hcn3, Kcnn3, Kcnd3, Kcna2, Kcna3, and Kcna10). This result supports the hypothesis that the deficit of aortic elastin content in the BN rat could be explained by anomalies in intracellular potassium concentration ([K + ] i ).Abstract-Hypertension is a cardiovascular disorder that appears in more than half of the patients with Williams-Beuren syndrome, hemizygous for the elastin gene among 26 to 28 other genes. It was shown that the antihypertensive drug minoxidil, an ATP-dependent potassium channel opener, enhances elastic fiber formation; however, no wide clinical application was developed because of its adverse side effects. The Brown Norway rat was used here as an arterial elastin-deficient model. We tested 3 different potassium channel openers, minoxidil, diazoxide, and pinacidil, and 1 potassium channel blocker, glibenclamide, on cultured smooth muscle cells from Brown Norway rat aorta. All tested potassium channel openers increased mRNAs encoding proteins and enzymes involved in elastic fiber formation, whereas glibenclamide had the opposite effect. The higher steady-state level of tropoelastin mRNA in minoxidil-treated cells was attributable to an increase in both transcription and mRNA stability. Treatment of Brown Norway rats for 10 weeks with minoxidil or diazoxide increased elastic fiber content and decreased cell number in the aortic media, without changing collagen content. The minoxidil-induced card...

In response to metabolic or environmental stress, cells activate powerful defense mechanisms to prevent the formation and accumulation of toxic protein aggregates. The main orchestrator of this cellular response is HSF1 (heat shock factor 1), a transcription factor involved in the up-regulation of protein-coding genes with protective roles. It has become very clear that HSF1 has a broader function than initially expected. Indeed, our previous work demonstrated that, upon stress, HSF1 activates the transcription of a non-coding RNA, named Satellite III, at pericentromeric heterochromatin. Here, we observe that the function of HSF1 extends to telomeres and identify subtelomeric DNA as a new genomic target of HSF1. We show that the binding of HSF1 to subtelomeric regions plays an essential role in the upregulation of non-coding TElomeric Repeat containing RNA (TERRA) transcription upon heat shock. Importantly, our data show that telomere integrity is impacted by heat shock and that telomeric DNA damages are markedly enhanced in HSF1 deficient cells. Altogether, our findings reveal a new direct and essential function of HSF1 in the transcriptional activation of TERRA and in telomere protection upon stress.