Low-dose Dasatinib Ameliorates Hypertrophic Cardiomyopathy in Noonan Syndrome with Multiple Lentigines.

Purpose: Noonan syndrome with multiple lentigines (NSML) is an autosomal dominant disorder presenting with hypertrophic cardiomyopathy (HCM). Up to 85% of NSML cases are caused by mutations in the PTPN11 gene that encodes for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2). We previously showed that low-dose dasatinib protects from the development of cardiac fibrosis in a mouse model of NSML harboring a Ptpn11 mutation.

Generation of a hypoxia-sensing mouse model.

Oxygen (O ) homeostasis is essential to the metazoan life. O -sensing or hypoxia-regulated molecular pathways are intimately involved in a wide range of critical cellular functions and cell survival from embryogenesis to adulthood. In this report, we have designed an innovative hypoxia sensor (O CreER) based on the O -dependent degradation domain of the hypoxia-inducible factor-1α and Cre recombinase.

Polycystin 2-dependent cardio-protective mechanisms revealed by cardiac stress.

Although autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple kidney cysts, the most frequent cause of death in ADPKD patients is cardiovascular disease. ADPKD is linked to mutations in PKD1 or pkd2, the genes that encode for the proteins polycystin 1 and polycystin 2 (PC1 and PC2, respectively). The cardiovascular complications have been assumed to be a consequence of renal hypertension and activation of renin/angiotensin/aldosterone (RAAS) pathway.

Endothelial HIF-1α Enables Hypothalamic Glucose Uptake to Drive POMC Neurons.

Glucose is the primary driver of hypothalamic proopiomelanocortin (POMC) neurons. We show that endothelial hypoxia-inducible factor 1α (HIF-1α) controls glucose uptake in the hypothalamus and that it is upregulated in conditions of undernourishment, during which POMC neuronal activity is decreased. Endothelium-specific knockdown of HIF-1α impairs the ability of POMC neurons to adapt to the changing metabolic environment in vivo, resulting in overeating after food deprivation in mice.

Low-dose dasatinib rescues cardiac function in Noonan syndrome.

Noonan syndrome (NS) is a common autosomal dominant disorder that presents with short stature, craniofacial dysmorphism, and cardiac abnormalities. Activating mutations in the gene encoding for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) causes approximately 50% of NS cases. In contrast, NS with multiple lentigines (NSML) is caused by mutations that inactivate SHP2, but it exhibits some overlapping abnormalities with NS.

Endothelial Nogo-B regulates sphingolipid biosynthesis to promote pathological cardiac hypertrophy during chronic pressure overload.

We recently discovered that endothelial Nogo-B, a membrane protein of the ER, regulates vascular function by inhibiting the rate-limiting enzyme, serine palmitoyltransferase (SPT), in de novo sphingolipid biosynthesis. Here, we show that endothelium-derived sphingolipids, particularly sphingosine-1-phosphate (S1P), protect the heart from inflammation, fibrosis, and dysfunction following pressure overload and that Nogo-B regulates this paracrine process. SPT activity is upregulated in banded hearts in vivo as well as in TNF-α-activated endothelium in vitro, and loss of Nogo removes the brake on SPT, increasing local S1P production.

Smooth Muscle Hypoxia-Inducible Factor 1α Links Intravascular Pressure and Atherosclerosis--Brief Report.

Objective: We hypothesized that the hypoxia-inducible factor (HIF) 1α in vascular smooth muscle contributes to the development of atherosclerosis, and links intravascular pressure to this process.

Approach And Results: Transverse aortic constriction was used to create high-pressure vascular segments in control, apolipoprotein E (ApoE)(-/-), smooth muscle-HIF1α(-/-), and ApoE(-/-)×smooth muscle-HIF1α(-/-) double-knockout mice. Transverse aortic constriction selectively induced atherosclerosis in high-pressure vascular segments in young ApoE(-/-) mice on normal chow, including coronary plaques within 1 month.

Interferon-γ-mediated allograft rejection exacerbates cardiovascular disease of hyperlipidemic murine transplant recipients.

Rationale: Transplantation, the most effective therapy for end-stage organ failure, is markedly limited by early-onset cardiovascular disease (CVD) and premature death of the host. The mechanistic basis of this increased CVD is not fully explained by known risk factors.

Objective: To investigate the role of alloimmune responses in promoting CVD of organ transplant recipients.

Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure.

Endothelial dysfunction is a critical factor in many cardiovascular diseases, including hypertension. Although lipid signaling has been implicated in endothelial dysfunction and cardiovascular disease, specific molecular mechanisms are poorly understood. Here we report that Nogo-B, a membrane protein of the endoplasmic reticulum, regulates endothelial sphingolipid biosynthesis with direct effects on vascular function and blood pressure.

Thioredoxin-2 inhibits mitochondrial reactive oxygen species generation and apoptosis stress kinase-1 activity to maintain cardiac function.

Background: Thioredoxin 2 (Trx2) is a key mitochondrial protein that regulates cellular redox and survival by suppressing mitochondrial reactive oxygen species generation and by inhibiting apoptosis stress kinase-1 (ASK1)-dependent apoptotic signaling. To date, the role of the mitochondrial Trx2 system in heart failure pathogenesis has not been investigated.

Methods And Results: Western blot and histological analysis revealed that Trx2 protein expression levels were reduced in hearts from patients with dilated cardiomyopathy, with a concomitant increase in ASK1 phosphorylation/activity.

Activation of hypoxia-inducible factor-2 in adipocytes results in pathological cardiac hypertrophy.

Background: Obesity can cause structural and functional abnormalities of the heart via complex but largely undefined mechanisms. Emerging evidence has shown that obesity results in reduced oxygen concentrations, or hypoxia, in adipose tissue. We hypothesized that the adipocyte hypoxia-signaling pathway plays an essential role in the development of obesity-associated cardiomyopathy.

Hypoxia-inducible factor-1α in vascular smooth muscle regulates blood pressure homeostasis through a peroxisome proliferator-activated receptor-γ-angiotensin II receptor type 1 axis.

Hypertension is a major worldwide health issue for which only a small proportion of cases have a known mechanistic pathogenesis. Of the defined causes, none have been directly linked to heightened vasoconstrictor responsiveness, despite the fact that vasomotor tone in resistance vessels is a fundamental determinant of blood pressure. Here, we reported a previously undescribed role for smooth muscle hypoxia-inducible factor-1α (HIF-1α) in controlling blood pressure homeostasis.

IL-13 receptor α2-arginase 2 pathway mediates IL-13-induced pulmonary hypertension.

Although previous literature suggests that interleukin (IL)-13, a T-helper type 2 cell effector cytokine, might be involved in the pathogenesis of pulmonary hypertension (PH), direct proof is lacking. Furthermore, a potential mechanism underlying IL-13-induced PH has never been explored. This study's goal was to investigate the role and mechanism of IL-13 in the pathogenesis of PH.

Normal glucose uptake in the brain and heart requires an endothelial cell-specific HIF-1α-dependent function.

Although intimately positioned between metabolic substrates in the bloodstream and the tissue parenchymal cells that require these substrates, a major role of the vascular endothelium in the regulation of tissue metabolism has not been widely appreciated. We hypothesized that via control of transendothelial glucose transport and contributing paracrine mechanisms the endothelium plays a major role in regulating organ and tissue glucose metabolism. We further hypothesized that the hypoxia-inducible factor -1α (HIF-1α) plays an important role in coordinating these endothelial functions.

Cellularity and structure of fresh human coronary thrombectomy specimens; presence of cells with markers of progenitor cells.

Acute coronary syndromes and acute myocardial infarctions are often related to plaque rupture and the formation of thrombi at the site of the rupture. We examined fresh coronary thrombectomy specimens from patients with acute coronary syndromes and assessed their structure and cellularity. The thrombectomy specimens consisted of platelets, erythrocytes and inflammatory cells.

Engineered zinc-finger proteins can compensate genetic haploinsufficiency by transcriptional activation of the wild-type allele: application to Willams-Beuren syndrome and supravalvular aortic stenosis.

Williams-Beuren syndrome (WBS) and supravalvular aortic stenosis (SVAS) are genetic syndromes marked by the propensity to develop severe vascular stenoses. Vascular lesions in both syndromes are caused by haploinsufficiency of the elastin gene. We used these distinct genetic syndromes as models to evaluate the feasibility of using engineered zinc-finger protein transcription factors (ZFPs) to achieve compensatory expression of haploinsufficient genes by inducing augmented expression from the remaining wild-type allele.

A designed zinc-finger transcriptional repressor of phospholamban improves function of the failing heart.

Selective inhibition of disease-related proteins underpins the majority of successful drug-target interactions. However, development of effective antagonists is often hampered by targets that are not druggable using conventional approaches. Here, we apply engineered zinc-finger protein transcription factors (ZFP TFs) to the endogenous phospholamban (PLN) gene, which encodes a well validated but recalcitrant drug target in heart failure.

miR-1 mediated suppression of Sorcin regulates myocardial contractility through modulation of Ca2+ signaling.

MicroRNAs are negative gene regulators and play important roles in cardiac development and disease. As evident by cardiomyopathy following cardiac-specific Dicer knockdown they also are required for maintaining normal cardiac contractile function but the specific role of miR-1 in the process is poorly understood. To characterize the role of miR-1 in particular and to identify its specific targets we created a tamoxifen-inducible, cardiac-specific Dicer knockdown mouse and demonstrated that Dicer downregulation results in a dramatic and rapid decline in cardiac function concurrent with significantly reduced levels of miR-1.

Inhibition of microRNA-29 enhances elastin levels in cells haploinsufficient for elastin and in bioengineered vessels--brief report.

Objective: The goal of this study was to determine whether antagonizing microRNA (miR)-29 enhances elastin (ELN) levels in cells and tissues lacking ELN.

Methods And Results: miR-29 mimics reduced ELN levels in fibroblasts and smooth muscle cells, whereas miR-29 inhibition increased ELN levels. Antagonism of miR-29 also increased ELN levels in cells from patients haploinsufficient for ELN and in bioengineered human vessels.

Inhibition of intimal hyperplasia after stenting by over-expression of p15: a member of the INK4 family of cyclin-dependent kinase inhibitors.

We evaluated the role of p15(Ink4), a member of the INK4 family of CDK inhibitors on vascular smooth muscle cells (VSMCs) proliferation, cell cycle progression and intimal hyperplasia after stenting. Aortic VSMCs transduced with either adenovirus encoding for p15(Ink4) or β-galactosidase were assessed for DNA synthesis, cell cycle progression, and pRb phosphorylation. Rabbit carotid arteries were stented and treated with peri-adventitial delivery of saline or adenovirus encoding for p15(Ink4) or β-galactosidase.

VEGF receptor 2 endocytic trafficking regulates arterial morphogenesis.

VEGF is the key growth factor regulating arterial morphogenesis. However, molecular events involved in this process have not been elucidated. Synectin null mice demonstrate impaired VEGF signaling and a marked reduction in arterial morphogenesis.