Enhancing natriuretic peptide signaling in adipose tissue, but not in muscle, protects against diet-induced obesity and insulin resistance.

In addition to controlling blood pressure, cardiac natriuretic peptides (NPs) can stimulate lipolysis in adipocytes and promote the "browning" of white adipose tissue. NPs may also increase the oxidative capacity of skeletal muscle. To unravel the contribution of NP-stimulated metabolism in adipose tissue compared to that in muscle in vivo, we generated mice with tissue-specific deletion of the NP clearance receptor, NPRC, in adipose tissue ( ) or in skeletal muscle ( ).

Early sensitization of myofilaments to Ca2+ prevents genetically linked dilated cardiomyopathy in mice.

Background: Dilated cardiomoypathies (DCM) are a heterogeneous group of inherited and acquired diseases characterized by decreased contractility and enlargement of cardiac chambers and a major cause of morbidity and mortality. Mice with Glu54Lys mutation in α-tropomyosin (Tm54) demonstrate typical DCM phenotype with reduced myofilament Ca2+ sensitivity. We tested the hypothesis that early sensitization of the myofilaments to Ca2+ in DCM can prevent the DCM phenotype.

Inwardly rectifying K channels are major contributors to flow-induced vasodilatation in resistance arteries.

Key Points: Endothelial inwardly rectifying K (Kir2.1) channels regulate flow-induced vasodilatation via nitric oxide (NO) in mouse mesenteric resistance arteries. Deficiency of Kir2.

VS-501: A NOVEL, NON-ABSORBED, CALCIUM- AND ALUMINUM-FREE, HIGHLY EFFECTIVE PHOSPHATE BINDER DERIVED FROM NATURAL PLANT POLYMER.

Inadequate control of serum phosphate in chronic kidney disease can lead to pathologies of clinical importance. Effectiveness of on-market phosphate binders is limited by safety concerns and low compliance due to high pill size/burden and gastrointestinal discomfort. VS-501 is a non-absorbed, calcium- and aluminum-free, chemically-modified, plant-derived polymer.

Desensitization of myofilaments to Ca2+ as a therapeutic target for hypertrophic cardiomyopathy with mutations in thin filament proteins.

Background: Hypertrophic cardiomyopathy (HCM) is a common genetic disorder caused mainly by mutations in sarcomeric proteins and is characterized by maladaptive myocardial hypertrophy, diastolic heart failure, increased myofilament Ca(2+) sensitivity, and high susceptibility to sudden death. We tested the following hypothesis: correction of the increased myofilament sensitivity can delay or prevent the development of the HCM phenotype.

Methods And Results: We used an HCM mouse model with an E180G mutation in α-tropomyosin (Tm180) that demonstrates increased myofilament Ca(2+) sensitivity, severe hypertrophy, and diastolic dysfunction.

Long-term rescue of a familial hypertrophic cardiomyopathy caused by a mutation in the thin filament protein, tropomyosin, via modulation of a calcium cycling protein.

We have recently shown that a temporary increase in sarcoplasmic reticulum (SR) cycling via adenovirus-mediated overexpression of sarcoplasmic reticulum ATPase (SERCA2) transiently improves relaxation and delays hypertrophic remodeling in a familial hypertrophic cardiomyopathy (FHC) caused by a mutation in the thin filament protein, tropomyosin (i.e., α-TmE180G or Tm180).

Effects of nicotine administration in a mouse model of familial hypertrophic cardiomyopathy, α-tropomyosin D175N.

The effects of nicotine (NIC) on normal hearts are fairly well established, yet its effects on hearts displaying familial hypertrophic cardiomyopathy have not been tested. We studied both the acute and chronic effects of NIC on a transgenic (TG) mouse model of FHC caused by a mutation in α-tropomyosin (Tm; i.e.

Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant genetic disorder linked to numerous mutations in the sarcomeric proteins. The clinical presentation of FHC is highly variable, but it is a major cause of sudden cardiac death in young adults with no specific treatments. We tested the hypothesis that early intervention in Ca(2+) regulation may prevent pathological hypertrophy and improve cardiac function in a FHC displaying increased myofilament sensitivity to Ca(2+) and diastolic dysfunction.

Rescue of familial cardiomyopathies by modifications at the level of sarcomere and Ca2+ fluxes.

Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that frequently show inappropriate ventricular hypertrophy or dilation. Current data suggest that numerous mutations in several genes can cause cardiomyopathies, and the severity of their phenotypes is also influenced by modifier genes. Two major types of inherited cardiomyopathies include familial hypertrophic cardiomyopathy (FHC) and dilated cardiomyopathy (DCM).

Changes in end-to-end interactions of tropomyosin affect mouse cardiac muscle dynamics.

The ends of striated muscle tropomyosin (TM) are integral for thin filament cooperativity, determining the cooperative unit size and regulating the affinity of TM for actin. We hypothesized that altering the alpha-TM carboxy terminal overlap end to the beta-TM counterpart would affect the amino-terminal association, which would alter the end-to-end interactions of TM molecules in the thin filament regulatory strand and affect the mechanisms of cardiac muscle contraction. To test this hypothesis, we generated transgenic (TG) mouse lines that express a mutant form of alpha-TM in which the first 275 residues are from alpha-TM and the last nine amino acids are from beta-TM (alpha-TM9aaDeltabeta).

Arginine-glycine-aspartic acid (RGD)-containing peptides inhibit the force production of mouse papillary muscle bundles via alpha 5 beta 1 integrin.

Integrins are considered to be an important mechanosensor in cardiac myocytes. To test whether integrins can influence cardiac contractile function, the force-frequency relationships of mouse papillary muscle bundles were measured in the presence or absence of a synthetic integrin-binding peptide, GRGDNP (gly-arg-gly-asp-asn-pro). Results demonstrate that in the presence of an arginine-glycine-aspartic acid (RGD)-containing synthetic peptide, contractile force was depressed significantly by, 28% at 4 Hz, 37.

Charged residue alterations in the inner-core domain and carboxy-terminus of alpha-tropomyosin differentially affect mouse cardiac muscle contractility.

Two important charge differences between the alpha- and beta-tropomyosin (TM) isoforms are the exchange of a serine residue in the inner-core region at position 229, and a histidine residue at the carboxy-terminal end at position 276, with glutamic acid and asparagine, respectively. We have recently shown that altering these two residues in alpha-TM to their beta-TM counterparts in transgenic (TG) mouse hearts causes a depression in both +dP/dt and -dP/dt and a decrease in calcium sensitivity. In this study, we address whether independent charge changes at these two residues in alpha-TM modulate cardiac function differentially.

Roles of phosphorylation of myosin binding protein-C and troponin I in mouse cardiac muscle twitch dynamics.

A normal heart increases its contractile force with increasing heart rate. Although calcium handling and myofibrillar proteins have been implicated in maintaining this positive force-frequency relationship (FFR), the exact mechanisms by which it occurs have not been addressed. In this study, we have developed an analytical method to define the calcium-force loop data, which characterizes the function of the contractile proteins in response to calcium that is independent of the calcium handling proteins.

Charged residue changes in the carboxy-terminus of alpha-tropomyosin alter mouse cardiac muscle contractility.

Striated muscle tropomyosin (TM) is an essential thin filament protein that is sterically and allosterically involved in calcium-mediated cardiac contraction. We have previously shown that overexpressing the beta-TM isoform in mouse hearts leads to physiological changes in myocardial relaxation and Ca(2+) handling of myofilaments. Two important charge differences in beta-TM compared to alpha-TM are the exchange of serine and histidine at positions 229 and 276 with glutamic acid and asparagine, respectively, imparting a more negative charge to beta-TM relative to alpha-TM.