Paulo Castro-Chaves

Physiological, pathological and potential therapeutic roles of adipokines

Formerly regarded purely as passive energy storage, adipose tissue is now recognized as a vital endocrine organ. Adipocytes secrete diverse peptide hormones named adipokines, which act in a autocrine, paracrine or endocrine way to influence several biological functions. Adipokines comprise diverse bioactive substances, including cytokines, growth, and complement factors, which perform essential regulatory functions related to energy balance, satiety and immunity. Presently adipokines have been widely implicated in obesity, diabetes, hypertension and cardiovascular diseases. In this article we aim to present a brief description of the roles and potential therapeutic modulation of adipokines, such as leptin, resistin, adiponectin, apelin, visfatin, FABP-4, tumor necrosis factor-α (TNF-α), interleukin-6 and plasminogen activator inhibitor-1 (PAI-1).

Inotropic and lusitropic effects of ghrelin and their modulation by the endocardial endothelium, NO, prostaglandins, GHS-R1a and KCa channels.

Contractile effects of ghrelin (10(-9) to 10(-6) M) were tested in rat papillary muscles of normal (n = 50) and hypertrophic (n = 16) right ventricles (RV). RV hypertrophy was induced by pulmonary hypertension using monocrotaline. In normal muscles, ghrelin was added either alone (n = 9) or after pre-treatment with indomethacin (cycloxygenase inhibitor, 10(-5) M; n = 10), L-nitro-L-arginin (NO synthase inhibitor, 10(-4) M; n = 9), D-Lys(3)-GHRP-6 (GHS-R1a antagonist; 10(-4) M; n = 8) or apamin+charybdotoxin (KCa channels blockers; 10(-6) M, n =7 ), as well as after damaging the endocardial endothelium (n = 7). In hypertrophic muscles, ghrelin was added either alone (n = 9) or after pre-treatment with apamin+charybdotoxin (10(-6 M, n=7). Ghrelin concentration-dependently decreased active tension (AT) and maximal velocity of tension rise (negative inotropic effect), as well as, maximal velocity of tension decay (negative lusitropic effect) and time to AT (onset of relaxation). These effects were maximal at 10(-6) M, similar in normal and hypertrophic muscles and were significantly altered only by apamin+charybdotoxin, indomethacin and L-nitro-L-arginin. Apamin+charybdotoxin attenuated the negative inotropic effect, while indomethacin and L-nitro-L-arginin, respectively, blunted and exacerbated the premature onset of relaxation. In conclusion, ghrelin induces negative inotropic and lusitropic effects and an earlier onset of relaxation in normal and hypertrophic myocardium, which are independent of GHS-R1a, since they were not affected by D-Lys(3)-GHRP-6. The negative inotropic effect is partly mediated by KCa channels, while the earlier onset of relaxation is modulated by prostaglandins and NO.

Angiotensin II acutely decreases myocardial stiffness: a novel AT1, PKC and Na+/H+ exchanger-mediated effect.

Acute effects of angiotensin II (AngII) on diastolic properties of the myocardium were investigated. Increasing concentrations of AngII (10−9 to 10−5 M) were added to rabbit papillary muscles in the absence (n=11) or presence of: (i) AT1 receptor antagonists, losartan (10−6 M; n=7) or ZD‐7155 (10−7 M; n=8); (ii) ZD‐7155 (10−7 M) plus AT2 receptor antagonist PD‐123,319 (2 × 10−6 M; n=6); (iii) PKC inhibitor, chelerythrine (10−5 M; n=8); or (iv) Na+/H+ exchanger (NHE) inhibitor, 5‐(N‐methyl‐N‐isobutyl)‐amiloride (10−6 M; n=10). Passive length–tension relations were constructed before and after a single concentration of AngII (10−5 M, n=6). Effects of AngII infusion (10 μg kg−1 min−1) were evaluated in in situ rabbit hearts. AngII concentration dependently increased inotropy and resting muscle length (RL). At 10−5 M, active tension increased 43.3±6.25% and RL 1.96±0.4%. Correcting RL to its initial value resulted in a 46±4% decrease of resting tension, indicating decreased muscle stiffness, as confirmed by the right and downward shift of the passive length–tension relation promoted by AngII. In the intact heart, at matched systolic pressures of 112 mmHg, AngII decreased end‐diastolic pressures from 10.3±0.3 to 5.9±0.5 mmHg, and minimal diastolic pressures from 8.4±0.5 to 4.6±0.6 mmHg. AT1 blockade inhibited AngII effects on myocardial inotropy and stiffness, while PKC or NHE inhibition only significantly attenuated its effects on resting length and tension. In conclusion, AngII decreases myocardial stiffness, an effect that requires AT1 receptor activation and is mediated by PKC and NHE. This represents a novel mechanism of acute neurohumoral modulation of diastolic function, suggesting that AngII is a powerful regulator of cardiac filling.

New pathways of the renin-angiotensin system: the role of ACE2 in cardiovascular pathophysiology and therapy.

Importance of the field: The renin-angiotensin system (RAS) is nowadays an important target in cardiovascular diseases and we are currently on the verge of a new interpretation of its role in cardiovascular homeostasis, mainly due to the identification of the new axis ACE2/angiotensin 1 - 7/Mas receptor. Areas covered in this review: The main aspects related to ACE2 role in cardiovascular physiology and possible pathological and therapeutic implications are reviewed. What the reader will gain: A description of the new view of the RAS, along with the key findings that support it. In the cardiovascular system, the ACE2/angiotensin 1 - 7/Mas axis, mainly through the inhibition of fibrosis, inflammation, thrombosis and cell proliferation, modulates RAS activity with significant pathophysiological implications in clinical conditions such as hypertension, myocardial ischemia and heart failure. A more complete understanding of this axis has significant therapeutic relevance and a major effort is being carried out in order to pursue this objective. Take home message: There is increasing evidence that ACE2/angiotensin 1 - 7/Mas receptor axis has a key role in RAS activity regulation with significant pathophysiological implications in several disease states. A therapeutic intervention at this level may open new doors and change the current approach to RAS targeting.

Neuregulin-1 improves right ventricular function and attenuates experimental pulmonary arterial hypertension

AIMS Pulmonary arterial hypertension (PAH) is a serious disease that affects both the pulmonary vasculature and the right ventricle (RV). Current treatment options are insufficient. The cardiac neuregulin (NRG)-1/ErbB system is deregulated during heart failure, and treatment with recombinant human NRG-1 (rhNRG-1) has been shown to be beneficial in animal models and in patients with left ventricular (LV) dysfunction. This study aimed to evaluate the effects of rhNRG-1 in RV function and pulmonary vasculature in monocrotaline (MCT)-induced PAH and RV hypertrophy (RVH). METHODS AND RESULTS Male wistar rats (7- to 8-weeks old, n = 78) were injected with MCT (60 mg/kg, s.c.) or saline and treated with rhNRG-1 (40 µg/kg/day) or vehicle for 1 week, starting 2 weeks after MCT administration. Another set of animals was submitted to pulmonary artery banding (PAB) or sham surgery, and followed the same protocol. MCT administration resulted in the development of PAH, pulmonary arterial and RV remodelling, and dysfunction, and increased RV markers of cardiac damage. Treatment with rhNRG-1 attenuated RVH, improved RV function, and decreased RV expression of disease markers. Moreover, rhNRG-1 decreased pulmonary vascular remodelling and attenuated MCT-induced endothelial dysfunction. The anti-remodelling effects of rhNRG-1 were confirmed in the PAB model, where rhNRG-1 treatment was able to attenuate PAB-induced RVH. CONCLUSION rhNRG-1 treatment attenuates pulmonary arterial and RV remodelling, and dysfunction in a rat model of MCT-induced PAH and has direct anti-remodelling effects on the pressure-overloaded RV.

Angiotensin II‐induced increase in myocardial distensibility and its modulation by the endocardial endothelium in the rabbit heart

As recently demonstrated, angiotensin II (Ang II) induces an increase in myocardial distensibility. Although endothelin‐1 and the endocardial endothelium (EE) also modulate myocardial diastolic properties, their interaction with Ang II at this level has not yet been investigated. Increasing concentrations of Ang II (from 10−8 to 10−5m) were studied in rabbit right papillary muscles in the following conditions: (1) baseline; (2) after selective removal of EE with Triton X‐100; and (3) with intact EE in presence of a non‐selective endothelin receptor antagonist (PD‐145065), a selective endothelin type A receptor antagonist (BQ‐123), an inhibitor of nitric oxide synthesis (NG‐nitro‐l‐arginine (l‐NA) or an inhibitor of the NAD(P)H oxidase (apocynin). At baseline, Ang II induced a concentration‐dependent positive inotropic effect and an increase in passive muscle length (L) up to 1.020 ± 0.004L/Lmax. After restoring muscle length to maximal physiological length (Lmax), passive tension decreased by 46.1 ± 4.0%. When the EE was removed, the effect on myocardial distensibility was abolished. With intact EE in presence of PD‐145065, BQ‐123 or l‐NA, the effects of Ang II on myocardial distensibility were attenuated, with a maximal increase in passive muscle length of 1.0087 ± 0.0012, 1.0068 ± 0.0022 and 1.0066 ± 0.0020L/Lmax and a decrease in resting tension of 22.6 ± 3.6, 16.1 ± 6.0 and 20.4 ± 5.6%, respectively. In the presence of apocynin, the effect on myocardial distensibility was abolished. In conclusion, the Ang II‐dependent acute increase in myocardial distensibility is abolished by the selective removal of the EE and attenuated in the presence of endothelin‐1 receptor antagonists, an inhibitor of nitric oxide synthesis or an inhibitor of NAD(P)H oxidase.

Acute modulation of myocardial function by angiotensin 1–7

Angiotensin 1-7 is a bioactive heptapeptide of the renin-angiotensin system. Its cardiovascular actions have recently acquired growing relevance, mainly due to its counter-regulatory actions in the angiotensin cascade. The aim of the present study was to evaluate the actions of angiotensin 1-7 on myocardial function. Increasing concentrations of angiotensin 1-7 (10(-9) to 10(-5)M) were added to rabbit right papillary muscles: (1) in baseline conditions with intact endocardial endothelium (EE); (2) after selective removal of the EE with Triton X-100 (1s, 0.01%); (3) with intact EE in the presence of the Mas receptor antagonist A-779, the AT(1) receptor antagonist ZD-7155, the AT(2) receptor antagonist PD-123,319 or the nitric oxide synthesis inhibitor NG-nitro-l-arginine (l-NA). Concerning the effects on contractility, we observed a significant decrease on active tension, dT/dt(max), peak shortening and dL/dt(max) of -10.5+/-3.6%, -8.0+/-3.0%, -5.3+/-2.6% and -5.7+/-2.3%, respectively. There was no change on relaxation parameters, namely dT/dt(min) or dL/dt(min). Time to half relaxation was significantly decreased. The presence of ZD-7155 or PD-123,319 did not change these effects. However, angiotensin 1-7 effects on myocardial properties were abolished after selective EE removal and in the presence of A-779 or l-NA. In conclusion, in this animal species, angiotensin 1-7 through its binding to Mas receptor induces a negative inotropic effect modulated by the EE and nitric oxide and independent of AT(1) or AT(2) receptors activation. As the effects described in the present work were influenced by the endocardial endothelium, they may be disrupted in situations associated to endothelial dysfunction, as in heart failure or myocardial ischemia.

Relaxin serum levels in acute heart failure are associated with pulmonary hypertension and right heart overload

Despite the promising results of serelaxin as a new potential acute heart failure (HF) therapy, its clinical use preceded the understanding of the endogenous relaxin system in HF. We aimed to evaluate relaxin circulating levels in a population of acute HF and their association with clinical and echocardiographic parameters.

Heart failure. Statins for all

Although there is increasing evidence of benefit in using statins to treat patients with non‐ischaemic heart failure, it is not yet possible to recommend the routine use of these drugs in all heart failure patients, irrespective of the aetiology

Are circulating relaxin levels related to pulmonary hypertension in patients with heart failure? A reply

We read with great interest the research letter from Emmens et al.1 and thank the authors for their comments on our recently published paper in this journal.2 Emmens et al. evaluated relaxin circulating levels in a cohort of patients with heart failure (HF) with preserved ejection fraction (HFpEF) and pulmonary hypertension (PH) and found no association between relaxin groups and echocardiographically or invasively determined intracardiac pressures.1 These results do not extend our recent findings that relaxin circulating levels were associated with clinical and echocardiographic markers of volume overload, PH and right heart dysfunction and overload in a population of acute HF patients.2 Several differences between the study populations are worth noting and may help to elucidate the differences between the results of the two studies. We evaluated relaxin levels at admission in a population of patients with acute HF, including both patients with HFpEF and those with HF with reduced ejection fraction.2 These patients were heterogeneous with respect to the degree of volume overload, volume distribution and echocardiographic parameters of chamber dimensions and function, which allowed us to establish different patterns of pulmonary pressures and right heart overload among relaxin groups.2 In the study by Emmens et al.,1 all patients had chronic HFpEF with established PH. This patient selection criterion may, on one hand, have hindered the establishment of differences in pulmonary and right heart pressures between groups. However, on the other hand, it supports our hypothesis of increased relaxin secretion to circulation in states of PH as relaxin levels in these patients (median: 82.3 pg/mL)1 were higher than have .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. been described in most previous studies addressing relaxin levels in HF, including our own. The lack of relaxin levels below the detection limit of the assay,1 unlike in our study in which levels were undetectable in about 25% of patients,2 also strengthens this hypothesis. In line with the promising results of serelaxin clinical trials in HF,3,4 increasing evidence suggests a role for endogenous relaxin in HF pathophysiology. The hypothesis of a compensatory up-regulation of the relaxin system in states of PH and of a role for this system in the modulation of pulmonary vasculature is compelling based on the available evidence,2,4,5 but further studies are needed to corroborate it. Better understanding of the role of endogenous relaxin in the pathophysiology of acute and chronic HF may be of great value in terms of expanding the therapeutic use of serelaxin in this context.