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Sepsis is a prevalent life-threatening condition related to a systemic infection, and with unresolved issues including refractory septic shock and organ failures. Endogenously released catecholamines are often inefficient to maintain blood pressure, and low reactivity to exogenous catecholamines with risk of sympathetic overstimulation is well documented in septic shock. In this context, apelinergics are efficient and safe inotrope and vasoregulator in rodents. However, their utility in a larger animal model as well as the limitations with regards to the enzymatic breakdown during sepsis, need to be investigated. The therapeutic potential and degradation of apelinergics in sepsis were tested experimentally and in a cohort of patients. (1) 36 sheep with or without fecal peritonitis-induced septic shock (a large animal experimental design aimed to mimic the human septic shock paradigm) were evaluated for hemodynamic and renal responsiveness to incremental doses of two dominant apelinergics: apelin-13 (APLN-13) or Elabela (ELA), and (2) 52 subjects (33 patients with sepsis/septic shock and 19 healthy volunteers) were investigated for early levels of endogenous apelinergics in the blood, the related enzymatic degradation profile, and data regarding sepsis outcome. APLN-13 was the only one apelinergic which efficiently improved hemodynamics in both healthy and septic sheep. Endogenous apelinergic levels early rose, and specific enzymatic breakdown activities potentially threatened endogenous apelin system reactivity and negatively impacted the outcome in human sepsis. Short-term exogenous APLN-13 infusion is helpful in stabilizing cardiorenal functions in ovine septic shock; however, this ability might be impaired by specific enzymatic systems triggered during the early time course of human sepsis. Strategies to improve resistance of APLN-13 to degradation and/or to overcome sepsis-induced enzymatic breakdown environment should guide future works.

Cardiomyocyte hypertrophy is regulated by several factors, including the ADP-ribosylation factor (Arf) family of small G proteins, among others. For instance, ArfGAP with dual pleckstrin homology domains 1 (Adap1) exerts an anti-hypertrophic effect in cultured cardiomyocytes. Its homologous protein, Adap2, is also expressed in the heart but its role remains elusive. To elucidate its function, we investigated the effects of adenoviral-mediated overexpression of Adap2 in cultured neonatal rat ventricular myocytes under both basal and pro-hypertrophic conditions, employing a range of microscopy and biochemical techniques. Despite minimal detection in neonatal rat hearts, Adap2 was found to be well expressed in adult rat hearts, being predominantly localized at the membrane fraction. In contrast to Adap1, overexpression of Adap2 provokes the robust accumulation of β1-integrin at the cellular surface of cultured cardiomyocytes. Interestingly, overexpressed Adap2 relocalizes at the sarcolemma and increases the size of cardiomyocytes upon phenylephrine stimulation, despite attenuating Erk1/2 phosphorylation and Nppa gene expression. Under these same conditions, cardiomyocytes overexpressing Adap2 also express higher level of detyrosinated tubulin, a marker of hypertrophic response. These findings provide new insights into the pro-hypertrophic function of Adap2 in cardiomyocytes.

Antagonists of L-type Ca²⁺ channels (LTCCs) have been used to treat human cardiovascular diseases for decades. However, these inhibitors can have untoward effects in patients with heart failure, and their overall therapeutic profile remains nebulous given differential effects in the vasculature when compared with those in cardiomyocytes. To investigate this issue, we examined mice heterozygous for the gene encoding the pore-forming subunit of LTCC (calcium channel, voltage-dependent, L type, α1C subunit [Cacna1c mice; referred to herein as α1C⁻/⁺ mice]) and mice in which this gene was loxP targeted to achieve graded heart-specific gene deletion (termed herein α1C-loxP mice). Adult cardiomyocytes from the hearts of α1C⁻/⁺ mice at 10 weeks of age showed a decrease in LTCC current and a modest decrease in cardiac function, which we initially hypothesized would be cardioprotective. However, α1C⁻/⁺ mice subjected to pressure overload stimulation, isoproterenol infusion, and swimming showed greater cardiac hypertrophy, greater reductions in ventricular performance, and greater ventricular dilation than α1C⁺/⁺ controls. The same detrimental effects were observed in α1C-loxP animals with a cardiomyocyte-specific deletion of one allele. More severe reductions in α1C protein levels with combinatorial deleted alleles produced spontaneous cardiac hypertrophy before 3 months of age, with early adulthood lethality. Mechanistically, our data suggest that a reduction in LTCC current leads to neuroendocrine stress, with sensitized and leaky sarcoplasmic reticulum Ca²⁺ release as a compensatory mechanism to preserve contractility. This state results in calcineurin/nuclear factor of activated T cells signaling that promotes hypertrophy and disease.

Catecholamines, in concert with fluid resuscitation, have long been recommended in the management of septic shock. However, not all patients respond positively and controversy surrounding the efficacy-to-safety profile of catecholamines has emerged, trending toward decatecholaminization. Contextually, it is time to re-examine the “maintaining blood pressure” paradigm by identifying safer and life-saving alternatives. We put in perspective the emerging and growing knowledge on a promising alternative avenue: the apelinergic system. This target exhibits invaluable pleiotropic properties, including inodilator activity, cardio-renal protection, and control of fluid homeostasis. Taken together, its effects are expected to be greatly beneficial for patients in septic shock.

Objectives: Arterial hypertension, when exacerbated by excessive dietary salt intake, worsens the morbidity and mortality rates associated with cardiovascular and renal diseases. Stimulation of the apelinergic system appears to protect against several circulatory system diseases, but it remains unknown if such beneficial effects are conserved in severe hypertension. Therefore, we aimed at determining whether continuous infusion of apelinergic ligands (i.e., Apelin-13 and Elabela) exerted cardiorenal protective effects in spontaneously hypertensive (SHR) rats receiving high-salt diet. Methods: A combination of echocardiography, binding assay, histology, and biochemical approaches were used to investigate the cardiovascular and renal effects of Apelin-13 or Elabela infusion over 6 weeks in SHR fed with normal-salt or high-salt chow. Results: High-salt intake upregulated the cardiac and renal expression of APJ receptor in SHR. Importantly, Elabela was more effective than Apelin-13 in reducing high blood pressure, cardiovascular and renal dysfunctions, fibrosis and hypertrophy in high-salt fed SHR. Unlike Apelin-13, the beneficial effects of Elabela were associated with a counter-regulatory role of the ACE/ACE2/neprilysin axis of the renin-angiotensin-aldosterone system (RAAS) in heart and kidneys of salt-loaded SHR. Interestingly, Elabela also displayed higher affinity for APJ in the presence of high salt concentration and better resistance to RAAS enzymes known to cleave Apelin-13. Conclusion: These findings highlight the protective action of the apelinergic system against salt-induced severe hypertension and cardiorenal failure. As compared with Apelin-13, Elabela displays superior pharmacodynamic and pharmacokinetic properties that warrant further investigation of its therapeutic use in cardiovascular and kidney diseases.

Increased levels of Ca 2+ in cardiomyocytes promote cell growth that, under stressful conditions, such as those caused by hypertension, can contribute to heart remodeling and failure. Joerg Heineke et al . identify a new regulator of this type of maladaptive cardiac muscle growth in mice, the calcium-binding protein CIB1, which they show regulates the membrane-association of calcineurin and downstream signaling. Hypertrophic heart disease is a leading health problem in Western countries. Here we identified the small EF hand domain–containing protein Ca 2+ and integrin–binding protein-1 (CIB1) in a screen for previously unknown regulators of cardiomyocyte hypertrophy. Yeast two-hybrid screening for CIB1-interacting partners identified a related EF hand domain–containing protein, calcineurin B, the regulatory subunit of the prohypertrophic protein phosphatase calcineurin. CIB1 localizes primarily to the sarcolemma in mouse and human myocardium, where it anchors calcineurin to control its activation in coordination with the L-type Ca 2+ channel. CIB1 protein amounts and membrane association were enhanced in cardiac pathological hypertrophy, but not in physiological hypertrophy. Consistent with these observations, Cib1 -deleted mice showed a marked reduction in myocardial hypertrophy, fibrosis, cardiac dysfunction and calcineurin–nuclear factor of activated T cells (NFAT) activity after pressure overload, whereas the degree of physiologic hypertrophy after swimming exercise was not altered. Transgenic mice with inducible and cardiac-specific overexpression of CIB1 showed enhanced cardiac hypertrophy in response to pressure overload or calcineurin signaling. Moreover, mice lacking Ppp3cb (encoding calcineurin A, β isozyme) showed no enhancement in cardiac hypertrophy associated with CIB1 overexpression. Thus, CIB1 functions as a previously undescribed regulator of cardiac hypertrophy through its ability to regulate the association of calcineurin with the sarcolemma and its activation.

1 Nitric oxide (NO) is known to affect the properties of various proteins via the S‐nitrosylation of cysteine residues. This study evaluated the direct effects of the NO donor sodium nitroprusside (SNP) on the pharmacological properties of the AT1 receptor for angiotensin II expressed in HEK‐293 cells. 2 SNP dose‐dependently decreased the binding affinity of the AT1 receptor without affecting its total binding capacity. This modulatory effect was reversed within 5 min of removing SNP. 3 The effect of SNP was not modified in the presence of the G protein uncoupling agent GTPγS or the soluble guanylyl cyclase inhibitor 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one. 4 The binding properties of a mutant AT1 receptor in which all five cysteine residues within the transmembrane domains had been replaced by serine was not affected by SNP. Systematic analysis of mutant AT1 receptors revealed that cysteine 289 conferred the sensitivity to SNP. 5 These results suggest that NO decreased the binding affinity of the AT1 receptor by S‐nitrosylation of cysteine 289. This modulatory mechanism may be particularly relevant in pathophysiological situations where the beneficial effects of NO oppose the deleterious effects of angiotensin II. British Journal of Pharmacology (2006) 148, 306–313. doi:10.1038/sj.bjp.0706725

Apelin serves as the endogenous ligand for the APJ receptor and enhances cardiac contractility without significantly affecting potassium currents. However, its short in vivo half-life limits clinical application, prompting the development of metabolically stable APJ receptor agonists. This study employed the patch-clamp technique to investigate the effects of the C-terminally modified apelin-13-2Nal derivative (2Nal) on action potential dynamics, rapid sodium (I ), and transient potassium (I ) currents in rat cardiomyocytes. We discovered that 2Nal prolongs ventricular action potential duration by selectively blocking I . Dose-response analysis indicated that 2Nal acts as a partial antagonist of I , achieving a maximum blockade of 47%, with an apparent EC50 of 0.3 nM, while not affecting I . Our lab previously found that an imbalance between I and I currents contributes to the development of cardiac arrhythmias in conditions like Brugada syndrome. Currently, few therapeutic options exist to safely address this imbalance, as sodium channel openers cannot restore it, and most I blockers are cardiotoxic. The selective blockade of I by 2Nal that we describe here helps restore the balance of electrical currents between I and I . Our study presents a novel, safe partial antagonist of I that may help prevent arrhythmias associated with Brugada syndrome.

Apelin serves as the endogenous ligand for the APJ receptor and enhances cardiac contractility without significantly affecting potassium currents. However, its short in vivo half-life limits clinical application, prompting the development of metabolically stable APJ receptor agonists. This study employed the patch-clamp technique to investigate the effects of the C-terminally modified apelin-13-2Nal derivative (2Nal) on action potential dynamics, rapid sodium (INa), and transient potassium (ITO) currents in rat cardiomyocytes. We discovered that 2Nal prolongs ventricular action potential duration by selectively blocking ITo. Dose-response analysis indicated that 2Nal acts as a partial antagonist of ITO, achieving a maximum blockade of 47%, with an apparent EC50 of 0.3 nM, while not affecting INa. Our lab previously found that an imbalance between ITo and INa currents contributes to the development of cardiac arrhythmias in conditions like Brugada syndrome. Currently, few therapeutic options exist to safely address this imbalance, as sodium channel openers cannot restore it, and most ITo blockers are cardiotoxic. The selective blockade of ITo by 2Nal that we describe here helps restore the balance of electrical currents between ITo and INa. Our study presents a novel, safe partial antagonist of ITo that may help prevent arrhythmias associated with Brugada syndrome.

The ArfGAP with dual PH domains 1 (ADAP1) regulates the activation of the hypertrophic mitogen-activated protein kinase ERK1/2 pathway in non-cardiomyocytes. However, its role in cardiomyocytes is unknown. Our aim was to characterize the role of ADAP1 in the hypertrophic process of cardiomyocytes. We assessed the expression of ADAP1 in the hearts of adult and neonatal rats by RT-qPCR and Western blotting and showed that it is preferentially expressed in cardiomyocytes. Adenoviral-mediated ADAP1 overexpression in cultured rat neonatal ventricular cardiomyocytes limited their serum-induced hypertrophic response as measured by immunofluorescence microscopy. Furthermore, ADAP1 overexpression completely blocked phenylephrine- and Mek1 constitutively active (Mek1ca) mutant-induced hypertrophy in these cells. The anti-hypertrophic effect of ADAP1 was not caused by a reduction in protein synthesis, interference with the Erk1/2 pathway, or disruption of the fetal gene program activation, as assessed by nascent protein labeling, Western blotting, and RT-qPCR, respectively. An analysis of cultured cardiomyocytes by confocal microscopy revealed that ADAP1 partially re-organizes α-actinin into dense puncta, a phenomenon that is synergized by Mek1ca overexpression. Biotin labeling of cell surface proteins from cardiomyocytes overexpressing ADAP1 revealed that it reduces the surface expression of β1-integrin, an effect that is strongly potentiated by Mek1ca overexpression. Our findings provide insights into the anti-hypertrophic function of ADAP1 in cardiomyocytes.