Therapeutic Strategy For Heart Failure Research Articles

Treatment with a CD31 agonist peptide improves the outcome of experimental heart failure with either reduced or preserved ejection fraction

CD31 is a mechanosensory receptor and recent studies in CD31 knockout mice have suggested a protective role for CD31 in condition of altered mechanic stress such as in heart failure. To directly assess the impact of CD31 signaling on the outcome of heart failure (HF) with both reduced and preserved ejection fraction (HFrEF and HFpEF, respectively). Permanent ligature of the proximal left coronary in C57Bl6 mice was used for modeling experimental HFrEF. Five days after surgery, mice displaying a myocardial infarction involving > 30% of the left ventricle (LV) at echocardiography were randomized to receive either a CD31 agonist peptide (P8RI, 2.5 mg/kg) or placebo by subcutaneous continuous infusion (osmotic pumps). Low dose angiotensin II infusion was applied to apolipoprotein E knockout (ApoE KO) mice as a model of HEpEF. The osmotic pumps delivered angiotensin II (200 μg/Kg/day) alone or together with P8RI. The Ejection Fraction (EF%) and the E/E’ ratio were evaluated by echocardiography. In the HFrEF model, the daily treatment with the CD31 agonist peptide starting from the 5th day after the myocardial infarction, improved both the EF% (68 ± 3% vs. 47 ± 4%, P = 0.05) evaluated 30 days later. Also, the LV filling pressure was improved by the treatment, as reflected by the E/E’ ratio (24.6 ± 2.4% vs. 49.7 ± 7.5, P = 0.05). An even more striking beneficial effect was observed in the model of HEpEF, in which the CD31 agonist treatment prevented the development of the diastolic LV dysfunction induced by the low dose of angiotensin II infusion as determined by the variation of the E/E’ ratio at the end of the treatment period (6 ± 7 in P8RI treated mice vs. 37 ± 8 in controls, P < 0.02). CD31 agonist drugs can contribute to improve function of the heart in experimental conditions of myocardial mechanic stress and may represent a novel therapeutic strategy for heart failure with both reduced and preserved ejection fraction.

Interleukin-10 stiffens the heart.

Cardiac-resident macrophages are a diverse population of cells that have a critical role in the pathogenesis of heart failure. A new understanding of communication between macrophages and cardiac fibroblasts could lead to novel therapeutic strategies for heart failure with preserved ejection function.

Genetic inhibition of the UPR gene Chac1 preserves cardiac function in a murine model of pressure overload induced heart failure

Introduction: The Unfolded Protein Response (UPR) is induced accompanying endoplasmic reticulum (ER) stress in cardiac myocytes, and has been implicated in the development of heart failure. Chac1 is a UPR induced gene, which directs enzymatic cleavage of intracellular glutathione and promotes cell death. Ablation of the Chac1 gene (Chac1-/-) in mice is lethal, whereas Chac1 heterozygous (Chac1+/−) mice were produced and are viable. Purpose: To investigate the effects of Chac1 haplo-insufficiency on cardiac structure and function in mice, in the setting of heart failure after aortic banding. Methods and Results: Chac1+/− and control (WT) mice (n ≥ 12) were subjected to aortic banding to induce pressure overload heart failure. After banding, the extent of cardiac dysfunction was evaluated using 2-D echocardiography, including ventricular hypertrophy and reduced cardiac output. At baseline, we found Chac1+/− mice had cardiac hypertrophy and increased ejection fraction (70 ±1 % vs 61 ±1 %, p < 0.01) compared to WT. Querying early time points 6-9 weeks after aortic banding, a parallel hypertrophic response occurred in Chac1+/− vs controls. Notably, by 15 weeks after aortic banding Chac1+/− mice had preserved cardiac ejection fraction (58±4 vs 36±2%, p < 0.01) compared to WT that had progressed into heart failure. Chac1+/− mice also displayed attenuated chamber dilation (LVEDD: 3.9 ±0.1 vs 4.5 ±0.1 mm p <0.01), lower normalized cardiac mass (9.6 ±0.3 vs 10.9 ±0.5, p<0.05), and reduced pulmonary edema (99 ±6 vs 120 ±3 mg fluid). Examining cardiac ventricle mRNA expression 15 weeks after TAC, Chac1+/− mice showed decreased Nppb (BNP), MLC2v, and Pin1 expressions versus WT. Conclusions: A benefit for Chac1 haplo-sufficiency in mice accompanying heart failure is revealed, evidenced by preserved cardiac structure and function. Additionally, Chac1+/− mice have increased cardiac mass and enhanced function at baseline, mimicking exercise-induced cardiac hypertrophy. Chac1 inhibition may represent a novel therapeutic strategy for heart failure, phenocopying the cardiac benefits of exercise.

High-density lipoprotein protects cardiomyocytes from oxidative stress via the PI3K/mTOR signaling pathway.

Low levels of plasma high‐density lipoprotein (HDL) cholesterol are associated with an increased risk of heart failure, regardless of the presence or absence of coronary artery disease. However, the direct effects of HDL on failing myocardium have not been fully elucidated. We found that HDL treatment resulted in improved cell viability in H9c2 cardiomyocytes under oxidative stress. This cardioprotective effect of HDL was regulated via the phosphatidylinositol 3‐kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. mTOR signaling promotes cell survival through the inactivation of the BCL2‐associated agonist of cell death via phosphorylation of ribosomal protein S6 kinase. Modulation of cardiac PI3K/mTOR signaling by HDL could represent a novel therapeutic strategy for heart failure.

Depletion of cardiac catecholamine stores impairs cardiac norepinephrine re-uptake by downregulation of the norepinephrine transporter.

In heart failure (HF), a disturbed cardiac norepinephrine (NE) homeostasis is characterized by depleted cardiac NE stores, impairment of the cardiac NE re-uptake by the neuronal norepinephrine transporter (NET) and enhanced cardiac NE net release. Reduced cardiac NE content appears to be caused by enhanced cardiac NE net release from sympathetic neurons in HF, triggered by neurohumoral activation. However, it remains unclear whether reduced NE itself has an impact on cardiac NE re-uptake, independent of neurohumoral activation. Here, we evaluated whether depletion of cardiac NE stores alone can regulate cardiac NE re-uptake. Treatment of Wistar rats with reserpine (5 mg/kg/d) for one (1d) or five days (5d) resulted in markedly reduced cardiac NE content, comparable to NE stores in experimental HF due to pressure overload. In order to assess cardiac NE re-uptake, the specific cardiac [3H]-NE uptake via the NET in a Langendorff preparation was measured. Reserpine treatment led to decreased NE re-uptake at 1d and 5d compared to saline treatment. Expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of the NE synthesis, was elevated in left stellate ganglia after reserpine. Mechanistically, measurement of NET mRNA expression in left stellate ganglia and myocardial NET density revealed a post-transcriptional downregulation of the NET by reserpine. In summary, present data demonstrate that depletion of cardiac NE stores alone is sufficient to impair cardiac NE re-uptake via downregulation of the NET, independent of systemic neurohumoral activation. Knowledge about the regulation of the cardiac NE homeostasis may offer novel therapeutic strategies in HF.

A Novel Approach to Identify the Role of Single Molecule Titin Mechanics in Human Heart Failure

Diastolic dysfunction occurs not only in diastolic heart failure, but also ubiquitously in systolic heart failure. A main determinant of diastolic passive tension is the elastic sarcomeric protein titin. The role of titin mechanics in diastolic dysfunction is not clearly understood. Here we developed a novel approach to detect mechanical properties of the elastic domain of single titin molecules from failing and non-failing human hearts. We further investigate the role of titin mechanics in heart failure by correlating clinical and biometric data from the corresponding human hearts, in conjunction with diastolic function of isolated human cardiomyocytes. Using atomic force microscopy, antibody specific tethering of the human native titin PEVK-distal Ig domain and the distal Ig domain alone was identified. Titin domains were stretched and released at different frequencies based on ventricular volume changes in the cardiac cycle. The nonlinear force tracings recorded from a series of linear stretch and release steps reflected titin viscoelasticity. Mean titin domain passive tension was measured in the range of 21.2 to 213.8 pN. The mechanical properties of the testing domains were significantly correlated with both the diastolic parameters measured in field-stimulated single cardiomyoyctes, and the biometric data of the corresponding human hearts. Our approach identified the mechanical properties of human native cardiac titin domains, and their relationship to the diastolic function of human hearts, up to single cell level. The current study provided insights into our understanding of cardiac relaxation kinetics in health and disease, contributing to the discovery of novel diagnostic and therapeutic strategies for heart failure.

Aging and homeostasis. Aging control through cardiac regenerative medicine.

Heart disease is one of the leading causes of death in the developed countries and various physical conditions in heart failure attribute to the impaired physical activities, which promotes aging. The principle cause of heart failure is the loss of self-renewal ability of cardiomyocytes in various injuries such as myocardial infarction. The replacement of injured tissues with the regenerated human myocardial tissues using technologies on tissue engineering and iPS cell will provide us the novel therapeutic strategy for heart failure and the related aging issues.

Activation of PPAR-α in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure.

Failing heart loses its metabolic flexibility, relying increasingly on glucose as its preferential substrate and decreasing fatty acid oxidation (FAO). Peroxisome proliferator-activated receptor α (PPAR-α) is a key regulator of this substrate shift. However, its role during heart failure is complex and remains unclear. Recent studies reported that heart failure develops in the heart of myosin heavy chain-PPAR-α transgenic mice in a manner similar to that of diabetic cardiomyopathy, whereas cardiac dysfunction is enhanced in PPAR-α knockout mice in response to chronic pressure overload. We created a pressure-overload heart failure model in mice through transverse aortic constriction (TAC) and activated PPAR-α during heart failure using an inducible transgenic model. After 8 wk of TAC, left ventricular (LV) function had decreased with the reduction of PPAR-α expression in wild-type mice. We examined the effect of PPAR-α induction during heart failure using the Tet-Off system. Eight weeks after the TAC operation, LV construction was preserved significantly by PPAR-α induction with an increase in PPAR-α-targeted genes related to fatty acid metabolism. The increase of expression of fibrosis-related genes was significantly attenuated by PPAR-α induction. Metabolic rates measured by isolated heart perfusions showed a reduction in FAO and glucose oxidation in TAC hearts, but the rate of FAO preserved significantly owing to the induction of PPAR-α. Myocardial high-energy phosphates were significantly preserved by PPAR-α induction. These results suggest that PPAR-α activation during pressure-overloaded heart failure improved myocardial function and energetics. Thus activating PPAR-α and modulation of FAO could be a promising therapeutic strategy for heart failure.NEW & NOTEWORTHY The present study demonstrates the role of PPAR-α activation in the early stage of heart failure using an inducible transgenic mouse model. Induction of PPAR-α preserved heart function, and myocardial energetics. Activating PPAR-α and modulation of fatty acid oxidation could be a promising therapeutic strategy for heart failure.

Targeting the Cardiac Myofibroblast Secretome to Treat Myocardial Fibrosis in Heart Failure.

Therapeutic strategies for heart failure (HF) should increasingly consider measures directly targeting the myocardium itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. In this regard, a new view is emerging that proposes the direct intervention on the pathological structural remodeling of the myocardium as part of HF therapy. One hallmark myocardial lesion in HF is the diffuse accumulation of collagen fibers (namely, collagen type I) within the interstitium and around the microvasculature of the myocardium (ie, myocardial fibrosis [MF]). MF is the result of the predominance of collagen synthesis over its degradation as a result of the actions of a population of persistent metabolically active cells: the myofibroblasts. MF impairs cardiac function and contributes to the development and worsening of HF, in addition to facilitating arrhythmias and ischemia, and thus adversely influences the evolution and outcome of nearly all cardiac diseases.1 Therefore, MF regression is an unmet medical need, and the search for new drugs aiming its reversal is active. However, the efficacy and safety of novel antifibrotic strategies currently under investigation seem questionable.2 We thus propose a therapeutic approach based on targeting the cardiac myofibroblast secretome with already available drugs, which have proven to be both efficient in reducing MF and safe in protecting cardiac function. In addition, we will discuss how to identify those HF patients in whom these therapies can be more beneficial and thus should be personalized. Cardiac myofibroblasts are cells expressing α-smooth muscle actin microfilaments that originate from the differentiation of several cell types (including resident cardiac fibroblasts) under the influence of many local and systemic factors (Figure 1). Myofibroblasts exhibit a synthetic phenotype that includes a secretome consisting of molecules requisite to modify the quantity and quality of the myocardial collagen network and facilitate MF …

Cardiac-Specific Overexpression of Phosphodiesterase 2 (PDE2) in Mouse is Cardioprotective

Phosphodiesterase 2 (PDE2) is a dual substrate enzyme, hydrolyzing both cAMP and cGMP. We showed that myocardial PDE2 is upregulated in human and experimental heart failure (HF) while PDE3 and PDE4 are reduced. To explore the pathophysiological consequences of enhanced PDE2 activity, transgenic mice with a heart-specific overexpression of the PDE2A3 isoform (PDE2-TG) were generated.PDE2 activity was measuredin heart extractsby radioenzymatic assay. Sarcomere shortening, Ca2+ transients and L-type Ca2+ current (ICa,L) were recorded in adult ventricular cardiomyocytes from wild-type (WT) and PDE2-TG mice. SR Ca2+ leak was estimated with tetracaine (RyR blocker) and spontaneous Ca2+ waves (SCW) were recorded during 30s pacing pause. Intracellular cAMP level was measured with FRET. Phosphorylation level of excitation-contraction coupling (ECC) proteins was determined by Western Blot. Heart function was investigated by echocardiography and ECG-telemetry. Isoprenaline (ISO) was used to compare β-adrenergic (β-AR) response of all parameters in WT and PDE2-TG mice.cAMP and cGMP-PDE2 activity was strongly increased in PDE2-TG as compared to WT mice. Resting and maximal heart rate was markedly reduced in PDE2-TG mice. The β-AR stimulation of cell contractility, Ca2+ transient, ICa,L and [cAMP]i was severely blunted. PDE2-TG mice showed reduced SR Ca2+ leak and SCW (both at the cellular and in vivo levels), without changes in Ca2+ load as compared to WT during β-AR activation. PDE2-TG mice showed a lower basal phosphorylation of ECC proteins and have a longer lifespan than their WT littermates. All effects of PDE2 overexpression were reversed by PDE2 inhibitor, Bay-607550.Our results demonstrate that PDE2 plays a critical role in the regulation of cardiac ECC. PDE2 overexpression appears to protect the cardiomyocytes by reducing Ca2+-leakage and arrhythmias during β-AR stimulation. PDE2 may represent a new therapeutic strategy in heart failure.

Absence of coronary sinus tributaries in ischemic cardiomyopathy: An insight from multidetector computed tomography cardiac venographic study

ObjectiveCardiac resynchronization therapy (CRT) is an important therapeutic strategy in heart failure. However, there is a high incidence of lead implantation failure and suboptimal response, particularly in ischemic cardiomyopathy. This failure rate may partly be secondary to lack of suitable coronary sinus branches for lead implantation. We sought to assess the presence of coronary sinus (CS) tributaries in patients with ischemic and non-ischemic cardiomyopathy. Materials and methodsMultidetector computed tomography (MDCT) was performed in 100 patients: 25 coronary artery bypass graft (CABG) patients with impaired left ventricular ejection fraction (LVEF), 25 CABG patients with preserved LVEF, 25 patients with non-ischemic cardiomyopathy, and 25 controls. The presence of the CS and its tributaries, including the posterior interventricular vein (PIV), posterolateral vein (PLV), left marginal vein (LMV), and the anterior interventricular vein (AIV) was assessed. ResultsThe CS, PIV, and AIV were demonstrated in all patients, whereas presence of a PLV and LMV was identified in 68% and 48% of CABG patients with impaired LVEF, 96% and 68% of CABG patients with preserved LVEF, 92% and 80% of patients with non-ischemic cardiomyopathy, and 100% and 80% of controls (p = 0.001 and 0.046 for PLV and LMV, respectively). ConclusionsThis is the first report to demonstrate that the posterolateral vein and left middle vein, branches of the coronary sinus, are detectable in a significantly smaller number of CABG patients with impaired LVEF compared to controls, CABG with preserved LVEF, and non-ischemic cardiomyopathy. The absence of CS tributary veins in ischemic cardiomyopathy potentially hinders proper lead implantation and results in suboptimal CRT response.

The Failing Heart Relies on Ketone Bodies as a Fuel.

Significant evidence indicates that the failing heart is energy starved. During the development of heart failure, the capacity of the heart to utilize fatty acids, the chief fuel, is diminished. Identification of alternate pathways for myocardial fuel oxidation could unveil novel strategies to treat heart failure. Quantitative mitochondrial proteomics was used to identify energy metabolic derangements that occur during the development of cardiac hypertrophy and heart failure in well-defined mouse models. As expected, the amounts of proteins involved in fatty acid utilization were downregulated in myocardial samples from the failing heart. Conversely, expression of β-hydroxybutyrate dehydrogenase 1, a key enzyme in the ketone oxidation pathway, was increased in the heart failure samples. Studies of relative oxidation in an isolated heart preparation using ex vivo nuclear magnetic resonance combined with targeted quantitative myocardial metabolomic profiling using mass spectrometry revealed that the hypertrophied and failing heart shifts to oxidizing ketone bodies as a fuel source in the context of reduced capacity to oxidize fatty acids. Distinct myocardial metabolomic signatures of ketone oxidation were identified. These results indicate that the hypertrophied and failing heart shifts to ketone bodies as a significant fuel source for oxidative ATP production. Specific metabolite biosignatures of in vivo cardiac ketone utilization were identified. Future studies aimed at determining whether this fuel shift is adaptive or maladaptive could unveil new therapeutic strategies for heart failure.

Therapeutic Strategy for Heart Failure in Becker Muscular Dystrophy.

An error appeared in the article titled Therapeutic Strategy for Heart Failure in Becker Muscular Dystrophy by Koichi Kimura, Hiroyuki Morita, Akinori Nakamura, Katsu Takenaka, (Vol. 57, No. 5, 527-529, 2016). The name of the last author on page 527 and the back cover should be Masao and not Daimon Masao.

Errata: Therapeutic Strategy for Heart Failure in Becker Muscular Dystrophy.

An error appeared in the article titled "Therapeutic Strategy for Heart Failure in Becker Muscular Dystrophy" by Koichi Kimura, Hiroyuki Morita, Akinori Nakamura, Katsu Takenaka, Masao Daimon (Vol. 57, No. 5, 527-529, 2016). The name of the last author on page 527 and the back cover should be "Masao Daimon" and not "Daimon Masao".

Abstract 11554: Chronic Cenderitide Administration Improves Cardiorenal Function and Remodeling in Experimental Heart Failure

Introduction: Heart failure (HF) is a major health burden in which renal impairment worsens prognosis. Targeting the vicious cycle between heart and kidney may be a more optimal therapeutic strategy for HF. The cardiac natriuretic peptides have cardiorenal protective effects through their receptor GC-A and GC-B. We sought to determine the actions of chronic administration of the dual GC-A/GC-B agonist cenderitide (CD-NP) upon cardiorenal function in experimental HF. Hypothesis: Chronic cenderitide therapy will improve cardiorenal function in HF. Methods: Experimental canine HF was induced by rapid right ventricular pacing at 240 bpm for 10 days which mimics advanced overt HF in humans. Canines (n=5 of each group) were treated with or without cenderitide (Capricor Therapeutics) subcutaneous injection (SQ) twice per day (SQ-BID, 10 ug/kg/day), cenderitide continuous SQ pump (SQ-pump, 5 ng/kg/min), or oral enalapril (ACEi, 0.5 mg/kg/day) for 10 days from the beginning of pacing. We defined hemodynamics, echo parameters, circulating neurohumoral factors at day 11, and global gene profiles using RT-PCR microarrays related to the NP system, fibrosis, growth factors, and inflammation in left atrium which undergoes early remodeling in this model. Results: The SQ-pump group showed significantly less atrial and renal weights, higher cardiac output, glomerular filtration rate, and % ejection fraction, and lower systemic vascular resistance and plasma renin activity (all p&lt;0.05) without lowering mean arterial pressure (MAP), whereas SQ-BID and ACEi lacked these effects together with lowering MAP compared to untreated canines. Gene profile analyses showed gene related to inflammatory cytokines such as TNF-alpha, IL-1 beta, and ROCK-2, and apoptosis such as caspase 7, Fas ligand, C-Myc and TP53 were suppressed (all p&lt;0.05) in SQ-pump but not SQ-BID or ACEi compare to un-treated group. Conclusions: Continuous SQ administration of cenderitide demonstrated superior beneficial effects on cardiorenal function and remodeling together with inhibition of circulating renin and tissue inflammatory and apoptosis pathways. Our studies suggest that continuous administration of cenderitide may provide cardiorenal protection in the setting of advanced HF.

10 Sumoylation of essential cardiac signalling proteins: preliminary evidence

SUMOylation is a post-translational modification process involving conjugation of the SUMO protein (small ubiquitin-like modifiers) to lysine residues, which can affect protein structure, function and subcellular location. Previous studies by Hajjar et al . 1 have demonstrated SUMOylation of SERCA2a, a calcium transporting ATPase responsible for calcium ion reuptake during cardiac excitation contraction coupling. It has been shown that SUMOylation preserves the ATPase activity and stability of SERCA2a in both mouse and human cells and that levels of SUMO1 and the SUMOylation of SERCA2a itself is greatly reduced in heart failure. Moreover, reconstitution of SUMO1 via adeno-associated-virus-mediated gene delivery has been shown to maintain expression of SERCA2a as well as improving cardiac function in mice with heart failure. Using sequence analysis, we have identified putative SUMOylation sites on other cardiac signalling proteins (beta2 adrenoceptor, ryanodine receptor, cardiac troponin I, and l-type calcium channel) and present preliminary evidence using peptide array that SUMOylation of these sites may occur. As proof of concept we have raised a specific antibody against the SUMOylated form of cTNI and show that this reagent can recognise the SUMOylated form of the protein in cells. We speculate that SUMOylation of cardiac proteins may be utilised as a biomarker of heart disease or provide a platform for the design of novel therapeutic strategies for heart failure. Reference Kho C, Lee A, Jeong D, Oh JG, Chaanine AH, Kizana E, Park WJ, Hajjar RJ. SERCA2a (sarcoplasmic reticulum Ca2+ ATPase) cTNI (cardiac troponin I). Nature 2011;477:601–605

Myocardial NF-κB activation is essential for zebrafish heart regeneration

Heart regeneration offers a novel therapeutic strategy for heart failure. Unlike mammals, lower vertebrates such as zebrafish mount a strong regenerative response following cardiac injury. Heart regeneration in zebrafish occurs by cardiomyocyte proliferation and reactivation of a cardiac developmental program, as evidenced by induction of gata4 regulatory sequences in regenerating cardiomyocytes. Although many of the cellular determinants of heart regeneration have been elucidated, how injury triggers a regenerative program through dedifferentiation and epicardial activation is a critical outstanding question. Here, we show that NF-κB signaling is induced in cardiomyocytes following injury. Myocardial inhibition of NF-κB activity blocks heart regeneration with pleiotropic effects, decreasing both cardiomyocyte proliferation and epicardial responses. Activation of gata4 regulatory sequences is also prevented by NF-κB signaling antagonism, suggesting an underlying defect in cardiomyocyte dedifferentiation. Our results implicate NF-κB signaling as a key node between cardiac injury and tissue regeneration.

Improvements in Left Atrial Appendage Velocities Following Transcatheter Aortic Valve Replacement

Background: The natriuretic peptide family consists of atrial and b-type natriuretic peptide (ANP, BNP) and C-type natriuretic peptide (CNP). ANP and BNP are mainly produced in the heart and possess potent blood pressure lowering as well as natriuretic and diuretic actions through guanylyl cyclase receptor A (GC-A) and cGMP activation. Meanwhile, CNP is an endothelium and renal derived hormone of which its mature biological active form, CNP22, has the most robust cardiorenal anti-remodeling properties via GC-B activation and generation of cGMP compared to GC-A. Recently we reported that heart failure (HF) patients have increased plasma and markedly elevated urinary levels of a larger CNP molecular form, CNP53, which also is biologically active and generates cGMP through the GC-B receptor. Notably, preliminary studies have demonstrated that CNP53 is more biologically active and has renal enhancing actions in vivo, compared to CNP22. However, it remains unclear if CNP53’s biological and renal actions differ from that of BNP in vivo. Objectives: To define the cardiorenal and cGMP generating actions of CNP53, GC-B agonist, compared to BNP, a GC-A agonist, in vivo. Hypothesis: We hypothesize that CNP53 has cardiorenal and cGMP actions in vivo, but will exhibit less hypotension than BNP. Methods: Vehicle (V), an equimolar dose of BNP or CNP53 (Phoenix Pharmaceuticals, CA) was infused intravenously into anesthetized normal rats. Mean arterial blood pressure (MAP), glomerular filtration rate (GFR) and urinary sodium (Na) excretion were assessed. Plasma and urinary cGMP was determined by radioimmunoassay. Data are presented as Mean6SE. *p!0.05 between all groups. Results: During CNP53 and BNP infusion, plasma cGMP (V: 961, CNP53: 9164, BNP: 190637*, pmol/ml) and urinary cGMP excretion (V: 3366, CNP53: 176628, BNP: 5096124*, pmol/min) significantly increased compared to vehicle. Moreover, GFR (V: 4.860.3, CNP53: 5.760.2, BNP: 7.260.5*, ml/min/kg) and urinary Na excretion (V: 0.860.1, CNP53: 1.460.2, BNP: 2.460.1*,uEq/min) also significantly increased with CNP53 and BNP compared to vehicle. Notably, BNP had the greatest drop in MAP compared to vehicle and CNP53 (DMAP V: 2.06 3.0, CNP53: -4.062.7, BNP: -11.363.8*, mmHg). Conclusion: We report CNP53 exerts favorable cardiorenal and cGMP actions without excessive hypotension as seen with BNP. These findings support an emerging concept that CNP53 may be an alternative therapeutic strategy for HF, especially in the setting of hypotension, and this warrants further investigation.

A change of heart: oxidative stress in governing muscle function?

Redox/cysteine modification of proteins that regulate calcium cycling can affect contraction in striated muscles. Understanding the nature of these modifications would present the possibility of enhancing cardiac function through reversible cysteine modification of proteins, with potential therapeutic value in heart failure with diastolic dysfunction. Both heart failure and muscular dystrophy are characterized by abnormal redox balance and nitrosative stress. Recent evidence supports the synergistic role of oxidative stress and inflammation in the progression of heart failure with preserved ejection fraction, in concert with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signalling via modification of the giant protein titin. Although antioxidant therapeutics in heart failure with diastolic dysfunction have no marked beneficial effects on the outcome of patients, it, however, remains critical to the understanding of the complex interactions of oxidative/nitrosative stress with pro-inflammatory mechanisms, metabolic dysfunction, and the redox modification of proteins characteristic of heart failure. These may highlight novel approaches to therapeutic strategies for heart failure with diastolic dysfunction. In this review, we provide an overview of oxidative stress and its effects on pathophysiological pathways. We describe the molecular mechanisms driving oxidative modification of proteins and subsequent effects on contractile function, and, finally, we discuss potential therapeutic opportunities for heart failure with diastolic dysfunction.

P53-Induced inflammation exacerbates cardiac dysfunction during pressure overload

The rates of death and disability caused by severe heart failure are still unacceptably high. There is evidence that the sterile inflammatory response has a critical role in the progression of cardiac remodeling in the failing heart. The p53 signaling pathway has been implicated in heart failure, but the pathological link between p53 and inflammation in the failing heart is largely unknown. Here we demonstrate a critical role of p53-induced inflammation in heart failure. Expression of p53 was increased in cardiac endothelial cells and bone marrow cells in response to pressure overload, leading to up-regulation of intercellular adhesion molecule-1 (ICAM1) expression by endothelial cells and integrin expression by bone marrow cells. Deletion of p53 from endothelial cells or bone marrow cells significantly reduced ICAM1 or integrin expression, respectively, as well as decreasing cardiac inflammation and ameliorating systolic dysfunction during pressure overload. Conversely, overexpression of p53 in bone marrow cells led to an increase of integrin expression and cardiac inflammation that reduced systolic function. Norepinephrine markedly increased p53 expression in endothelial cells and macrophages. Reducing β2-adrenergic receptor expression in endothelial cells or bone marrow cells attenuated cardiac inflammation and improved systolic dysfunction during pressure overload. These results suggest that activation of the sympathetic nervous system promotes cardiac inflammation by up-regulating ICAM1 and integrin expression via p53 signaling to exacerbate cardiac dysfunction. Inhibition of p53-induced inflammation may be a novel therapeutic strategy for heart failure.