Mechanism of millisecond Lys48-linked poly-ubiquitin chain formation by cullin-RING ligases.

E3 ubiquitin ligases, in collaboration with E2 ubiquitin-conjugating enzymes, modify proteins with poly-ubiquitin chains. Cullin-RING ligase (CRL) E3s use Cdc34/UBE2R-family E2s to build Lys48-linked poly-ubiquitin chains to control an enormous swath of eukaryotic biology. Yet the molecular mechanisms underlying this exceptional linkage specificity and millisecond kinetics of poly-ubiquitylation remain unclear.

Multiomics analyses reveal dynamic bioenergetic pathways and functional remodeling of the heart during intermittent fasting.

Intermittent fasting (IF) has been shown to reduce cardiovascular risk factors in both animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction. However, the underlying molecular mechanisms behind these effects remain unclear. To shed light on the molecular and cellular adaptations of the heart to IF, we conducted comprehensive system-wide analyses of the proteome, phosphoproteome, and transcriptome, followed by functional analysis.

Caffeine prevents restenosis and inhibits vascular smooth muscle cell proliferation through the induction of autophagy.

Caffeine is among the most highly consumed substances worldwide, and it has been associated with decreased cardiovascular risk. Although caffeine has been shown to inhibit the proliferation of vascular smooth muscle cells (VSMCs), the mechanism underlying this effect is unknown. Here, we demonstrated that caffeine decreased VSMC proliferation and induced macroautophagy/autophagy in an vascular injury model of restenosis.

A neutralizing IL-11 antibody reduces vessel hyperplasia in a mouse carotid artery wire injury model.

Vascular restenosis remains a major problem in patients with coronary artery disease (CAD) and peripheral artery disease (PAD). Neointimal hyperplasia, defined by post-procedure proliferation and migration of vascular smooth muscle cells (VSMCs) is a key underlying pathology. Here we investigated the role of Interleukin 11 (IL-11) in a mouse model of injury-related plaque development.

Lipid efflux mechanisms, relation to disease and potential therapeutic aspects.

Lipids are hydrophobic and amphiphilic molecules involved in diverse functions such as membrane structure, energy metabolism, immunity, and signaling. However, altered intra-cellular lipid levels or composition can lead to metabolic and inflammatory dysfunction, as well as lipotoxicity. Thus, intra-cellular lipid homeostasis is tightly regulated by multiple mechanisms.

FURIN Inhibition Reduces Vascular Remodeling and Atherosclerotic Lesion Progression in Mice.

Objective- Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3; FURIN) as a member of several coronary artery disease-associated pathways. Thus, our objective is to determine the role of FURIN in atherosclerosis.

Estrogen but not testosterone preserves myofilament function from doxorubicin-induced cardiotoxicity by reducing oxidative modifications.

Here, we aimed to explore sex differences and the impact of sex hormones on cardiac contractile properties in doxorubicin (DOX)-induced cardiotoxicity. Male and female Sprague-Dawley rats were subjected to sham surgery or gonadectomy and then treated or untreated with DOX (2 mg/kg) every other week for 10 wk. Estrogen preserved maximum active tension (T) with DOX exposure, whereas progesterone and testosterone did not.

Significant role of estrogen in maintaining cardiac mitochondrial functions.

Increased susceptibility to stress-induced myocardial damage is a significant concern in addition to decreased cardiac performance in postmenopausal females. To determine the potential mechanisms underlying myocardial vulnerability after deprivation of female sex hormones, cardiac mitochondrial function is determined in 10-week ovariectomized rats (OVX). Significant mitochondrial swelling in the heart of OVX rats is observed.