Overcoming Insulin Insufficiency by Forced Follistatin Expression in β-cells of db/db Mice.

Diabetes poses a substantial burden to society as it can lead to serious complications and premature death. The number of cases continues to increase worldwide. Two major causes of diabetes are insulin resistance and insulin insufficiency.

Recovery from decompensated heart failure is associated with a distinct, phase-dependent gene expression profile.

Background: Clinical and experimental studies have traditionally focused on understanding the mechanisms for why a heart fails. We hypothesize that the pathways involved with myocardial recovery are not simply the reverse of those that cause heart failure. However, determining when and how a decompensated heart can recover remains unknown.

Enhancing muscle membrane repair by gene delivery of MG53 ameliorates muscular dystrophy and heart failure in δ-Sarcoglycan-deficient hamsters.

Muscular dystrophies (MDs) are caused by genetic mutations in over 30 different genes, many of which encode for proteins essential for the integrity of muscle cell structure and membrane. Their deficiencies cause the muscle vulnerable to mechanical and biochemical damages, leading to membrane leakage, dystrophic pathology, and eventual loss of muscle cells. Recent studies report that MG53, a muscle-specific TRIM-family protein, plays an essential role in sarcolemmal membrane repair.

The histone methyltransferase Set7/9 promotes myoblast differentiation and myofibril assembly.

The molecular events that modulate chromatin structure during skeletal muscle differentiation are still poorly understood. We report in this paper that expression of the H3-K4 histone methyltransferase Set7 is increased when myoblasts differentiate into myotubes and is required for skeletal muscle development, expression of muscle contractile proteins, and myofibril assembly. Knockdown of Set7 or expression of a dominant-negative Set7 mutant impairs skeletal muscle differentiation, accompanied by a decrease in levels of histone monomethylation (H3-K4me1).

Post-Natal knockdown of fukutin-related protein expression in muscle by long-termRNA interference induces dystrophic pathology [corrected].

Limb-girdle muscular dystrophy 2I (LGMD2I) is caused by mutations in the fukutin-related protein (FKRP) gene. Unlike its severe allelic forms, LGMD2I usually involves slower onset and milder course without defects in the central nervous system. The lack of viable animal models that closely recapitulate LGMD2I clinical phenotypes led us to use RNA interference technology to knock down FKRP expression via postnatal gene delivery so as to circumvent embryonic lethality.

Loss of microRNAs in neural crest leads to cardiovascular syndromes resembling human congenital heart defects.

Objective: Congenital heart defects represent the most common human birth defects. Even though the genetic cause of these syndromes has been linked to candidate genes, the underlying molecular mechanisms are still largely unknown. Disturbance of neural crest cell (NCC) migration into the derivatives of the pharyngeal arches and pouches can account for many of the developmental defects.

Periostin is a novel factor in cardiac remodeling after experimental and clinical unloading of the failing heart.

Background: Maladaptive left ventricular hypertrophy (LVH) remains a prevalent and highly morbid condition associated with end-stage heart disease. Originally evaluated in the context of bone development, periostin is important in endocardial cushion formation and has recently been implicated in heart failure. Because of its potential role in cardiovascular development, we sought to establish the role of periostin after relief of pressure overload in animal and human models.

MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice.

MicroRNAs (miRNAs) are a class of small noncoding RNAs that have gained status as important regulators of gene expression. Here, we investigated the function and molecular mechanisms of the miR-208 family of miRNAs in adult mouse heart physiology. We found that miR-208a, which is encoded within an intron of alpha-cardiac muscle myosin heavy chain gene (Myh6), was actually a member of a miRNA family that also included miR-208b, which was determined to be encoded within an intron of beta-cardiac muscle myosin heavy chain gene (Myh7).

Muscle ring finger 1 mediates cardiac atrophy in vivo.

Pathological cardiac hypertrophy, induced by various etiologies such as high blood pressure and aortic stenosis, develops in response to increased afterload and represents a common intermediary in the development of heart failure. Understandably then, the reversal of pathological cardiac hypertrophy is associated with a significant reduction in cardiovascular event risk and represents an important, yet underdeveloped, target of therapeutic research. Recently, we determined that muscle ring finger-1 (MuRF1), a muscle-specific protein, inhibits the development of experimentally induced pathological; cardiac hypertrophy.

Regression of pressure-induced left ventricular hypertrophy is characterized by a distinct gene expression profile.

Objective: Left ventricular hypertrophy is a highly prevalent and robust predictor of cardiovascular morbidity and mortality. Existing studies have finely detailed mechanisms involved with its development, yet clinical translation of these findings remains unsatisfactory. We propose an alternative strategy focusing on mechanisms of left ventricular hypertrophy regression rather than its progression and hypothesize that left ventricular hypertrophy regression is associated with a distinct genomic profile.

Inhibitory kappa B kinase-beta is a target for specific nuclear factor kappa B-mediated delayed cardioprotection.

Objective: Myocardial ischemia/reperfusion injury remains a vexing problem. Translating experimental strategies that deliver protective agents before the ischemic insult limits clinical applicability. We targeted 2 proteins in the nuclear factor-kappaB pathway, inhibitory kappa B kinase-beta, and 26S cardiac proteasome to determine their cardioprotective effects when delivered during reperfusion.

Myocardin inhibits cellular proliferation by inhibiting NF-kappaB(p65)-dependent cell cycle progression.

We previously reported the importance of the serum response factor (SRF) cofactor myocardin in controlling muscle gene expression as well as the fundamental role for the inflammatory transcription factor NF-kappaB in governing cellular fate. Inactivation of myocardin has been implicated in malignant tumor growth. However, the underlying mechanism of myocardin regulation of cellular growth remains unclear.

Proteasome inhibition promotes regression of left ventricular hypertrophy.

Current research in left ventricular hypertrophy (LVH) has largely focused on its progression and therapeutic mechanisms to prevent or slow its development. Few studies have centered on the regression or treatment of existing LVH. Nuclear factor-kappaB (NF-kappaB) is an inflammatory transcription factor that has been shown to be involved in LVH development.

IKKbeta inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury.

Despite years of experimental and clinical research, myocardial ischemia-reperfusion (IR) remains an important cause of cardiac morbidity and mortality. The transcription factor nuclear factor-kappaB (NF-kappaB) has been implicated as a key mediator of reperfusion injury. Activation of NF-kappaB is dependent upon the phosphorylation of its inhibitor, IkappaBalpha, by the specific inhibitory kappaB kinase (IKK) subunit, IKKbeta.

Coupling diurnal cytosolic Ca2+ oscillations to the CAS-IP3 pathway in Arabidopsis.

Various signaling pathways rely on changes in cytosolic calcium ion concentration ([Ca2+]i). In plants, resting [Ca2+]i oscillates diurnally. We show that in Arabidopsis thaliana, [Ca2+]i oscillations are synchronized to extracellular Ca2+ concentration ([Ca2+]o) oscillations largely through the Ca2+-sensing receptor CAS.

Nitric oxide represses the Arabidopsis floral transition.

The correct timing of flowering is essential for plants to maximize reproductive success and is controlled by environmental and endogenous signals. We report that nitric oxide (NO) repressed the floral transition in Arabidopsis thaliana. Plants treated with NO, as well as a mutant overproducing NO (nox1), flowered late, whereas a mutant producing less NO (nos1) flowered early.