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Curcumin, a polyphenolic compound derived from the widely used spice Curcuma longa, has shown anti-atherosclerotic effects in animal models and cultured vascular cells. Inflammation is a major contributor to atherosclerosis development and progression. We previously reported that the induction of the proinflammatory molecule TRAF3IP2 (TRAF3 Interacting Protein 2) or inhibition of the matrix metallopeptidase (MMP) regulator RECK (REversion Inducing Cysteine Rich Protein with Kazal Motifs) contributes to pro-oxidant, proinflammatory, pro-mitogenic and pro-migratory effects in response to external stimuli in vascular smooth muscle cells. Here we hypothesized that EF24, a curcumin analog with a better bioavailability and bioactivity profile, reverses interleukin (IL)-18-induced TRAF3IP2 induction, RECK suppression and the proinflammatory phenotype of primary human aortic smooth muscle cells (ASMC). The exposure of ASMC to functionally active recombinant human IL-18 (10 ng/mL) upregulated TRAF3IP2 mRNA and protein expression, but markedly suppressed RECK in a time-dependent manner. Further investigations revealed that IL-18 inhibited both miR-30a and miR-342 in a p38 MAPK- and JNK-dependent manner, and while miR-30a mimic blunted IL-18-induced TRAF3IP2 expression, miR-342 mimic restored RECK expression. Further, IL-18 induced ASMC migration, proliferation and proinflammatory phenotype switching, and these effects were attenuated by TRAF3IP2 silencing, and the forced expression of RECK or EF24. Together, these results suggest that the curcumin analog EF24, either alone or as an adjunctive therapy, has the potential to delay the development and progression of atherosclerosis and other vascular inflammatory and proliferative diseases by differentially regulating TRAF3IP2 and RECK expression in ASMC. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA), characterized by episodes of intermittent hypoxia (IH), is highly prevalent in patients with abdominal aortic aneurysm (AAA). However, whether IH serves as an independent risk factor for AAA development remains to be investigated. Here, we determined the effects of chronic (6 mo) IH on angiotensin (Ang II)-induced AAA development in C57BL/6J male mice and investigated the underlying mechanisms of IH in cultured vascular smooth muscle cells (SMCs). IH increased the susceptibility of mice to develop AAA in response to Ang II infusion by facilitating the augmentation of the abdominal aorta's diameter as assessed by transabdominal ultrasound imaging. Importantly, IH with Ang II augmented aortic elastin degradation and the expression of matrix metalloproteinases (MMPs), mainly MMP8, MMP12, and a disintegrin and metalloproteinase-17 (ADAM17) as measured by histology and immunohistochemistry. Mechanistically, IH increased the activities of MMP2, MMP8, MMP9, MMP12, and ADAM17, while reducing the expression of the MMP regulator reversion-inducing cysteine-rich protein with Kazal motifs (RECK) in cultured SMCs. Aortic samples from human AAA were associated with decreased RECK and increased expression of ADAM17 and MMPs. These data suggest that IH facilitates AAA development when additional stressors are superimposed and that this occurs in association with an increased presence of aortic MMPs and ADAM17, potentially due to IH-induced modulation of RECK expression. These findings support a plausible synergistic link between OSA and AAA and provide a better understanding of the molecular mechanisms underlying the pathogenesis of AAA. NEW & NOTEWORTHY: IH facilitates Ang II-induced abdominal aortic diameter expansion and AAA development in C57BL/6J male mice. IH upregulates the expression of specific MMPs such as MMP8, MMP12, and ADAM17. IH directly suppresses RECK expression and increases MMPs activity in SMCs. Human AAA tissues exhibit a downregulation of RECK and an upregulation of ADAM17 and MMPs. [ABSTRACT FROM AUTHOR]

Adverse cardiac remodeling contributes to heart failure development and progression, partly due to inappropriate sympathetic nervous system activation. Although b-adrenergic receptor (β-AR) blockade is a common heart failure therapy, not all patients respond, prompting exploration of alternative treatments. Minocycline, an FDA-approved antibiotic, has pleiotropic properties beyond antimicrobial action. Recent evidence suggests it may alter gene expression via changes in miRNA expression. Thus, we hypothesized that minocycline could prevent adverse cardiac remodeling induced by the β-AR agonist isoproterenol, involving miRNA-mRNA transcriptome alterations. Male C57BL/6J mice received isoproterenol (30 mg/kg/day sc) or vehicle via osmotic minipump for 21 days, along with daily minocycline (50 mg/kg ip) or sterile saline. Isoproterenol induced cardiac hypertrophy without altering cardiac function, which minocycline prevented. Total mRNA sequencing revealed isoproterenol altering gene networks associated with inflammation and metabolism, with fibrosis activation predicted by integrated miRNA-mRNA sequencing, involving miR-21, miR-30a, miR-34a, miR-92a, and miR-150, among others. Conversely, the cardiac miRNA-mRNA transcriptome predicted fibrosis inhibition in minocycline-treated mice, involving antifibrotic shifts in Atf3 and Itgb6 gene expression associated with miR-194 upregulation. Picrosirius red staining confirmed isoproterenol-induced cardiac fibrosis, prevented by minocycline. These results demonstrate minocycline's therapeutic potential in attenuating adverse cardiac remodeling through miRNA-mRNA-dependent mechanisms, especially in reducing cardiac fibrosis. NEW & NOTEWORTHY: We demonstrate that minocycline treatment prevents cardiac hypertrophy and fibrotic remodeling induced by chronic b-adrenergic stimulation by inducing antifibrotic shifts in the cardiac miRNA-mRNA transcriptome. [ABSTRACT FROM AUTHOR]