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Heart failure

Cardiac-targeted delivery of regulatory RNA molecules and genes for the treatment of heart failure
Wolfgang Poller, Roger Hajjar, Heinz-Peter Schultheiss, and Henry Fechner

Current strategies for regulatory RNA modulation. The cartoon outlines the principle of RNAi alongside that of miRNA enhancement, both of which share multiple cellular components (boxes on the right), as well as strategies towards miRNA inhibition (left).

Modulating fatty acid oxidation in heart failure

Lionetti V et al. Cardiovasc Res (2011) 90(2): 202-209 doi:10.1093/cvr/cvr038 - Click here to view the abstract


Cardiomyocyte substrates utilization. (A) Healthy cardiomyocyte. Cardiomyocyte mainly uses FAs that enter into the cell and are converted in the mitochondria through the carnitine palmitoyltransferase type 1 and type 2 (CPT-1 and CPT-2), and the carnitine acylcarnitine translocase (CT) before being used by β-oxidation (β-Ox) to produce FADH2, H22, reduced form of flavine adenine dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide.

Parathyroid hormone is a DPP-IV inhibitor and increases SDF-1-driven homing of CXCR4+ stem cells into the ischaemic heart

Huber BC et al. Cardiovasc Res (2011) 90(3): 529-537 doi:10.1093/cvr/cvr014 - Click here to view the abstract

Mechanism of PTH-mediated cardioprotection. PTH administration after MI induces mobilization of stem cells from the BM to the peripheral blood. These stem cells circulate to the damaged heart, where they are incorporated by interaction of intact myocardial SDF-1 and the homing receptor CXCR4. PTH inhibits DPP-IV activity and thereby prevents the degradation of intact SDF-1. Thus, an increased amount of SDF-1 improves homing of mobilized CXCR4+ cells. Altogether, PTH reduced cardiac remodelling after MI and enhanced cardiac function by attenuating the development of ischaemic cardiomyopathy.

KATP channel-dependent metaboproteome decoded: systems approaches to heart failure prediction, diagnosis, and therapy

Arrell DK et al. Cardiovasc Res (2011) 90(2): 258-266 doi:10.1093/cvr/cvr046 - Click here to view the abstract

Forecasting cardiac outcome from a presymptomatic proteomic signature. (A) At baseline, no differences were observed in cardiac structure or function between age- and sex-matched wild-type and Kir6.2 KATP channel knockout cohorts. Left ventricular tissue was extracted for proteomic analysis by comparative 2D gel electrophoresis resolution. (B) Statistical analysis of quantified 2D gel images indicated significant differences in 9% of detected protein species, subsequently isolated and identified by tandem mass spectrometry and categorized by primary protein function, revealing a metabolism-centric theme of protein change. (C) Altered proteins served as focus proteins for network analysis, with Ingenuity Pathways Knowledge Base expanding the KATP channel-dependent changes into a broader network neighbourhood, which reinforced the metabolic focus of measured changes both by ontological function (shown) and by ontological assessment of overrepresented biological processes (not shown).34

(D) Bioinformatic interrogation of proteome changes and their expanded network, for the presence of potential adverse effects, indicated an overrepresentation of markers associated with susceptibility to cardiac disease. Subsequent experimental imposition of graded stress validated disease susceptibility, with the Kir6.2 deficient cohort exhibiting progressively deleterious structural and functional cardiac defects, ultimately decreasing survival. *P< 0.05 vs. WT counterparts; **P< 0.01 vs. WT counterparts.

NO points to epigenetics in vascular development

Illi B et al. Cardiovasc Res (2011) 90(3): 447-456 doi:10.1093/cvr/cvr056 - Click here to view the abstract

Mechanism of PTH-mediated cardioprotection. PTH administration after MI induces mobilization of stem cells from the BM to the peripheral blood. These stem cells circulate to the damaged heart, where they are incorporated by interaction of intact myocardial SDF-1 and the homing receptor CXCR4. PTH inhibits DPP-IV activity and thereby prevents the degradation of intact SDF-1. Thus, an increased amount of SDF-1 improves homing of mobilized CXCR4+ cells. Altogether, PTH reduced cardiac remodelling after MI and enhanced cardiac function by attenuating the development of ischaemic cardiomyopathy.

Phosphatase-1 inhibitor-1 in physiological and pathological Β-adrenoceptor signalling

Wittköpper K et al. Cardiovasc Res (2011) 91(3): 392-401 doi:10.1093/cvr/cvr058 - Click here to view the abstract

Function and regulation of phosphatase-1-inhibitor-1 (I-1) and constitutively active I-1c.

Control of protein phosphorylation/dephosphorylation events occurs through regulation of protein kinases and phosphatases. The phosphatase type 1 comprises the main activity of Ser/Thr phosphatases in the heart. Inhibitor-1 (I-1) specifically inhibits phosphatase-1. I-1 was found to be downregulated in human heart failure but hyperactive in human atrial fibrillation, implicating I-1 in the pathogenesis of heart failure and arrhythmias. (A) I-1 represents a distal element of Β-adrenoceptor (AR) signalling, which allows amplification of protein kinase A (PKA)-mediated effects on the phosphorylation state of regulatory proteins. (B) I-1 consists of 171 amino acids (aa) and an N-terminal consensus motif (KIQF) that is essential for I-1 binding to phosphatase-1. I-1 becomes activated upon phosphorylation by cAMP-dependent PKA at Thr35, resulting in a potent inhibition of phosphatase-1. In contrast, phosphorylation at Ser67 by protein kinase Cα (PKCα) attenuates its inhibitory activity towards phosphatase-1. Phosphatase-2A (PP-2A) and Ca2+-dependent phosphatase-2B (PP-2B, calcineurin) dephosphorylate I-1 at Thr35 and thus reverses its inhibitory activity on phosphatase-1. (C) Replacement of Thr35 by phosphomimetic aspartic acid (T35D) and C-terminal truncation to 65 aa yields a constitutively active form of I-1 (I-1c) that is independent of PKA, PP-2A, and PP-2B.