Raloxifene attenuates Gas6 and apoptosis in experimental aortic valve disease in renal failure

Abstract

failure is associated with aortic valve calcification. Using our rat model of uremiainduced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in that disease. We also explored the effects of raloxifene, an estrogen receptor modulator, on valvular calcification. Gene array analysis was performed in aortic valves obtained from three groups of rats (n ϭ 7 rats/group): calcified valves obtained from rats fed with uremic diet, valves after calcification resolution following diet cessation, and control. In addition, four groups of rats (n ϭ 10 rats/group) were used to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet that also received daily raloxifene. Evaluation included imaging, histology, and antigen expression analysis. Gene array results showed that the majority of the altered expressed genes were in diet group valves. Most apoptosisrelated genes were changed in a proapoptotic direction in calcified valves. Apoptosis and decreases in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of survival pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. In conclusion, downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.growth arrest-specific 6; uremia CARDIOVASCULAR CALCIFICATION is one of the highest causes of morbidities and mortalities in patients with end-stage renal disease. These patients develop aortic valve calcification (AVC) and coronary calcification at an accelerated rate. Associated with this cardiovascular calcification are increased rates of myocardial infarctions and valvular heart disease. The pathogenesis of AVC in renal failure (RF) is not fully elucidated. It has been suggested that the process involves active osteoblast transformation of valve tissue, which results in increased formation of bone matrix (4, 25). Most of the data regarding the pathogenesis of AVC were obtained from animal models based on various components of the metabolic syndrome, emphasizing the role of atherogenesis in AVC (26, 37). In patients with RF, AVC and aortic stenosis are common and progress especially rapidly (18). The prevalence and extent of AVC in this population is poorly explained by traditional cardiovascular risk factors; abnormalities of mineral metabolism are likely to contribute to its development and progression. Current models of RF and accelerated calcification have demonstrated that calcium phosphate metabolism is critical for disease development (13), and inhibitors of calcification (fetuin A) are important in its prevention...

S100/Calgranulin-Mediated Inflammation Accelerates Left Ventricular Hypertrophy and Aortic Valve Sclerosis in Chronic Kidney Disease in a Receptor for Advanced Glycation End Products–Dependent Manner

“…As shown in Supplement Figure 1, neonatal cardiac fibroblasts from WT hearts did not increase FGF23 mRNA in response to high-phosphate medium supplemented either with rS100A12 (1ug/ml) or control BSA cultured for up to 20 days. As expected, genes important for the regulation of mineralization including osteocalcin (BGLAP), osteopontin (OPN) and Matrix gla protein (MGP), previously found at increased levels in calcific aortic valves of uremic animal models 29, 30 , increased in response to high-phosphate calcification medium. While rS100A12 did not alter expression of FGF23, rS100A12 reduced significantly gene expression of osteopontin by 20% to 40% (Supplement Figure 1C).…”

Effects of Raloxifene on the Proliferation and Apoptosis of Human Aortic Valve Interstitial Cells

“…RAL has certain effects on cardiovascular diseases, and previous studies revealed that RAL and other SERMs improve the function of vascular endothelial cells [19, 20], dilate the coronary artery [8, 21], and regulate blood fat [22]. However, only a few reports on basic and clinical studies of the effect of RAL on valvular heart disease have been published [23]. Based on the above discussion and description of many literatures, we found that the microsomal antiestrogen-binding site (AEBS) is a high-affinity membranous binding site for the antitumor drug RAL that selectively binds diphenylmethane derivatives of RAL such as PBPE (N-pyrrolidino-4-(phenylmethyphenoxyl)-ethanamine, HCl) and mediates their antiproliferative properties [24–26].…”

Poricoic acid A enhances melatonin inhibition of AKI-to-CKD transition by regulating Gas6/Axl NF κB/Nrf2 axis

“…The mechanisms underlying renal IRI are associated with the initiation of oxidative stress and inflammation, which are regulated by the growth arrest-specific 6 (Gas6) and its receptors Tyro3, Axl and MerTK, among which Gas6 exerts its anti-inflammatory effects mainly through Axl [4]. In acute stage, Gas6/Axl plays protective roles after IRI in multiple organs, including kidney, heart and liver [5].…”