Biomechanical stress and cytoskeletal remodeling are key determinants of cellular homeostasis and tissue responses to mechanical stimuli and injury. Here we document the increased activity of gelsolin, an actin filament severing and capping protein, in failing human hearts. Deletion of gelsolin prevents biomechanical stress-induced adverse cytoskeletal remodeling and heart failure in mice. We show that phosphatidylinositol (3,4,5)-triphosphate (PIP3) lipid suppresses gelsolin actin-severing and capping activities. Accordingly, loss of PI3Kα, the key PIP3-producing enzyme in the heart, increases gelsolin-mediated actin-severing activities in the myocardium in vivo, resulting in dilated cardiomyopathy in response to pressure-overload. Mechanical stretching of adult PI3Kα-deficient cardiomyocytes disrupts the actin cytoskeleton, which is prevented by reconstituting cells with PIP3. The actin severing and capping activities of recombinant gelsolin are effectively suppressed by PIP3. Our data identify the role of gelsolin-driven cytoskeletal remodeling in heart failure in which PI3Kα/PIP3 act as negative regulators of gelsolin activity.

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Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress inApln−/yaorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater inApln−/ymice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture inApln−/ymice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) inLdlr−/−mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases.

Perfluorooctane sulfonate (PFOS), a persistent and bioaccumulative compound, is widely distributed in the environment. To explore the molecular mechanism of neonatal neurotoxic effects, we evaluated the transcriptional effects of prenatal and neonatal exposure to PFOS in developing rat brain by performing gene expression profiling in the cerebral cortex. Dams received 3.2 mg/kg PFOS in their feed from gestational day 1 (GD1) to weaning (PND 21). Pups then had free access to treated feed until PND 35. Six Illumina RatRef-12 Expression BeadChips were used to identify gene expression changes on postnatal days (PNDs) 1, 7, and 35. Significantly affected genes (P < 0.05) were involved in neuroactive ligand-receptor interaction, calcium signaling pathways, cell communication, long-term potentiation/depression, the cell cycle, and peroxisome proliferator-activated receptor (PPAR) signaling. To compare prenatal and lactational exposure contributions to transcriptional effects, a subset of altered genes obtained from the gene-profile study that represented neurobiological functions was analyzed using RT-PCR in a follow-up cross-foster study lasting from PND1 to 21. Prenatal and postnatal exposure to PFOS caused potential neurotoxicity as demonstrated by developmentally different global transcriptional changes. Prenatal exposure was more effective in altering expression of several genes. Also, transcriptional effects of PFOS exposure on neurodevelopment occurred primarily by disrupting the neuroendocrine system.