Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of lysyl oxidase.

Arterial stiffening and cardiac dysfunction are hallmarks of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LaminA mouse model of HGPS recapitulates the premature arterial stiffening and early diastolic dysfunction seen in human HGPS. Lysyl oxidase (LOX) is up-regulated in the arteries of these mice, and treatment with the LOX inhibitor, β-aminopropionitrile, improves arterial mechanics and cardiac function.

MMP12 Deletion Preferentially Attenuates Axial Stiffening of Aging Arteries.

Arterial stiffening is a hallmark of aging, but how aging affects the arterial response to pressure is still not completely understood, especially with regard to specific matrix metalloproteinases (MMPs). Here, we performed biaxial inflation-extension tests on C57BL/6 mice to study the effects of age and MMP12, a major arterial elastase, on arterial biomechanics. Aging from 2 to 24 months leads to both circumferential and axial stiffening with stretch, and these changes are associated with an increased wall thickness, a decreased inner radius-wall thickness ratio, and a decreased in vivo axial stretch.

Cardiovascular protection in females linked to estrogen-dependent inhibition of arterial stiffening and macrophage MMP12.

Arterial stiffening is a consequence of aging and a cholesterol-independent risk factor for cardiovascular disease (CVD). Arterial stiffening and CVD show a sex bias, with men more susceptible than premenopausal women. How arterial stiffness and sex interact at a molecular level to confer risk of CVD is not well understood.

Matrix metalloproteinase-12 is an essential mediator of acute and chronic arterial stiffening.

Arterial stiffening is a hallmark of aging and risk factor for cardiovascular disease, yet its regulation is poorly understood. Here we use mouse modeling to show that matrix metalloproteinase-12 (MMP12), a potent elastase, is essential for acute and chronic arterial stiffening. MMP12 was induced in arterial smooth muscle cells (SMCs) after acute vascular injury.

miR-221/222 compensates for Skp2-mediated p27 degradation and is a primary target of cell cycle regulation by prostacyclin and cAMP.

p27(kip1) (p27) is a cdk-inhibitory protein with an important role in the proliferation of many cell types. SCF(Skp2) is the best studied regulator of p27 levels, but Skp2-mediated p27 degradation is not essential in vivo or in vitro. The molecular pathway that compensates for loss of Skp2-mediated p27 degradation has remained elusive.

Cell-type- and cell-cycle-specific anti-mitogenesis by cicaprost.

Stents eluting anti-proliferative drugs limit restenosis, but drugs commonly used to date are relatively non-specific cytostatic agents which inhibit proliferation of intimal endothelial cells as well as medial smooth muscle cells and may thereby contribute to the clinical complications associated with angioplasty. In an effort to identify a more specific anti-proliferative agent, we compared the effects of rapamycin to those of cicaprost, a mimetic of the naturally occurring anti-mitogen, PGI(2). Rapamycin and cicaprost were both strongly anti-mitogenic in vascular smooth muscle cells (VSMCs).

Cell-cycle control by physiological matrix elasticity and in vivo tissue stiffening.

Background: A number of adhesion-mediated signaling pathways and cell-cycle events have been identified that regulate cell proliferation, yet studies to date have been unable to determine which of these pathways control mitogenesis in response to physiologically relevant changes in tissue elasticity. In this report, we use hydrogel-based substrata matched to biological tissue stiffness to investigate the effects of matrix elasticity on the cell cycle.

Results: We find that physiological tissue stiffness acts as a cell-cycle inhibitor in mammary epithelial cells and vascular smooth muscle cells; subcellular analysis in these cells, mouse embryonic fibroblasts, and osteoblasts shows that cell-cycle control by matrix stiffness is widely conserved.

Hyaluronan and CD44 antagonize mitogen-dependent cyclin D1 expression in mesenchymal cells.

High molecular weight (HMW) hyaluronan (HA) is widely distributed in the extracellular matrix, but its biological activities remain incompletely understood. We previously reported that HMW-HA binding to CD44 antagonizes mitogen-induced S-phase entry in vascular smooth muscle cells (SMCs; Cuff, C.A.

Antimitogenic effects of HDL and APOE mediated by Cox-2-dependent IP activation.

HDL and its associated apo, APOE, inhibit S-phase entry of murine aortic smooth muscle cells. We report here that the antimitogenic effect of APOE maps to the N-terminal receptor-binding domain, that APOE and its N-terminal domain inhibit activation of the cyclin A promoter, and that these effects involve both pocket protein-dependent and independent pathways. These antimitogenic effects closely resemble those seen in response to activation of the prostacyclin receptor IP.