Stem cell therapy is a promising alternative approach to heart diseases. The most prevalent source of multipotent stem cells, usually called somatic or adult stem cells (mesenchymal stromal/stem ...cells, MSCs) used in clinical trials is bone marrow (BM-MSCs), adipose tissue (AT-MSCs), umbilical cord (UC-MSCs) and placenta. Therapeutic use of MSCs in cardiovascular diseases is based on the benefits in reducing cardiac fibrosis and inflammation that compose the cardiac remodeling responsible for the maintenance of normal function, something which may end up causing progressive and irreversible dysfunction. Many factors lead to cardiac fibrosis and failure, and an effective therapy is lacking to reverse or attenuate this condition. Different approaches have been shown to be promising in surpassing the poor survival of transplanted cells in cardiac tissue to provide cardioprotection and prevent cardiac remodeling. This review includes the description of pre-clinical and clinical investigation of the therapeutic potential of MSCs in improving ventricular dysfunction consequent to diverse cardiac diseases.
The relatively low efficacy of ACE‐inhibitors in the treatment of heart failure in women after estrogen loss may be due to their inability to reach the intracellular sites at which angiotensin (Ang) ...II is generated and/or the existence of cell‐specific mechanisms in which ACE is not the essential processing pathway for Ang II formation. We compared the metabolic pathway for Ang II formation in freshly isolated myocytes (CMs) and non‐myocytes (NCMs) in cardiac membranes extracted from hearts of gonadal‐intact and ovariectomized (OVX) adult WKY and SHR rats. Plasma Ang II levels were higher in WKY vs. SHR (strain effect: WKY: 62 ± 6 pg/ml vs. SHR: 42 ± 9 pg/ml; p < 0.01), independent of OVX. The enzymatic activities of chymase, ACE, and ACE2 were higher in NCMs versus CMs, irrespective of whether assays were performed in cardiac membranes from WKY or SHR or in the presence or absence of OVX. E2 depletion increased chymase activity, but not ACE activity, in both CMs and NCMs. Moreover, cardiac myocyte chymase activity associated with diastolic function in WKYs and cardiac structure in SHRs while no relevant functional and structural relationships between the classic enzymatic pathway of Ang II formation by ACE or the counter‐regulatory Ang‐(1‐7) forming path from Ang II via ACE2 were apparent. The significance of these novel findings is that targeted cell‐specific chymase rather than ACE inhibition may have a greater benefit in the management of HF in women after menopause.
Chymase‐mediated angiotensin II formation (or chymase activity) in cardiomyocyte cell membranes is linked to worsening of diastolic function, defined by increased Doppler‐derived filling pressures (E/e′), and increases in left ventricular (LV) mass in normotensive (WKY) and hypertensive (SHR) rats, respectively, after surgically induced menopause.
Background:
Diastolic dysfunction develops in response to hypertension and estrogen (E2) loss and is a forerunner to heart failure (HF) in women. The cardiac renin–angiotensin system (RAS) ...contributes to diastolic dysfunction, but its role with respect to E2 and blood pressure remain unclear.
Methods:
We compared the effects of ovariectomy (OVX) or sham surgery on the cardiac RAS, left ventricular (LV) structure/function, and systemic/intracardiac pressures of spontaneously hypertensive rats (SHRs: n = 6 intact and 6 OVX) and age-matched Wistar-Kyoto (WKY: n = 5 intact and 4 OVX) controls.
Results:
WKY rats were more sensitive to OVX than SHRs with respect to worsening of diastolic function, as reflected by increases in Doppler-derived filling pressures (E/e′) and reductions in myocardial relaxation (e′). This pathobiologic response in WKY rats was directly linked to increases in cardiac gene expression and enzymatic activity of chymase and modest reductions in ACE2 activity. No overt changes in cardiac RAS genes or activities were observed in SHRs, but diastolic function was inversely related to ACE2 activity.
Conclusion:
Endogenous estrogens exert a more significant regulatory role upon biochemical components of the cardiac RAS of WKY versus SHRs, modulating the lusitropic and structural components of its normotensive phenotype.
Background and Purpose
Pulmonary arterial hypertension (PAH) is a progressive disease associated with high morbidity and mortality, despite advances in medical therapy. We compared the effects of ...infigratinib (NVP‐BGJ398), a new FGF receptor‐1 inhibitor, with or without the PDE‐5 inhibitor sildenafil, on vascular function and remodelling as well as on gene expression of signal transducers for receptors of TGF‐β (Smads‐1/2/4) and transcription factor of endothelial–mesenchymal transition (Twist‐1) in established experimental PAH. Types I and III pro‐collagen and TGF‐β expressions in lung fibroblasts were analysed in vitro after the different treatments.
Experimental Approach
PAH was induced in male Wistar rats with monocrotaline. 14 days later, treatments sildenafil (SIL), infigratinib (INF) or their combination (SIL+INF) were given for another 14 days. On Day 28, echocardiography and haemodynamic assays were performed, and lungs and pulmonary vessels were removed for analysis by histology, immunohistochemistry and RT‐PCR. Fibroblasts prepared from PAH lungs were also analysed for TGF‐β and pro‐collagen.
Key Results
Only the combination of infigratinib and sildenafil significantly improved right ventricular systolic pressure and vascular remodelling parameters (right ventricular hypertrophy, smooth muscle α‐actin, vessel wall thickness, and vascular collagen content). Infigratinib may act by reducing gene expression of Smads‐1/4 and Twist‐1 in lung tissue, as well as TGF‐β and types I and III pro‐collagen in lung fibroblasts.
Conclusions and Implications
In this model of monocrotaline‐induced PAH, the combination of the new inhibitor of FGF receptor‐1, infigratinib, and sildenafil effectively improved haemodynamics and decreased vascular remodelling.
Vulvar rejuvenation, which includes both functional and aesthetic aspects, has received a lot of attention in recent years. Despite the fact that surgical interventions have proven to be effective, ...the development of minimally invasive techniques for restoring volume and tissue function remains a top priority. This case study describes a novel method for vulvar volumization and collagen stimulation of the labia majora using a hyaluronic acid filling technique. The procedure begins with a meticulous assessment of each patient's anatomical characteristics and specific concerns, followed by hyaluronic acid retroinjections using a microcannula. The current article describes the use of this technique on a single patient and emphasizes its potential benefits in addressing various vulvar concerns, with a focus on minimal downtime and high patient satisfaction. The case report adds to the ongoing search for optimal vulvar rejuvenation strategies by providing valuable insights into the efficacy and utility of this novel approach.
Heart Failure in Menopause: Treatment and New Approaches da Silva, Jaqueline S; Montagnoli, Tadeu Lima; de Sá, Mauro Paes Leme ...
International journal of molecular sciences,
2022-Dec-01, 2022-12-01, 20221201, Letnik:
23, Številka:
23
Journal Article
Recenzirano
Odprti dostop
Aging is an important risk factor for the development of heart failure (HF) and half of patients with HF have preserved ejection fraction (HFpEF) which is more common in elderly women. In general, ...sex differences that lead to discrepancies in risk factors and to the development of cardiovascular disease (CVD) have been attributed to the reduced level of circulating estrogen during menopause. Estrogen receptors adaptively modulate fibrotic, apoptotic, inflammatory processes and calcium homeostasis, factors that are directly involved in the HFpEF. Therefore, during menopause, estrogen depletion reduces the cardioprotection. Preclinical menopause models demonstrated that several signaling pathways and organ systems are closely involved in the development of HFpEF, including dysregulation of the renin-angiotensin system (RAS), chronic inflammatory process and alteration in the sympathetic nervous system. Thus, this review explores thealterations observed in the condition of HFpEF induced by menopause and the therapeutic targets with potential to interfere with the disease progress.
Estrogen receptors (ER) mediate functions beyond their endocrine roles, as modulation of cardiovascular, renal, and immune systems through anti-inflammatory and anti-apoptotic effects, preventing ...necrosis of cardiomyocytes and endothelial cells, and attenuating cardiac hypertrophy. Estradiol (E2) prevents cardiac dysfunction, increases nitric oxide synthesis, and reduces the proliferation of vascular cells, yielding protective effects, regardless of gender. Such actions are mediated by ER (ER-alpha (ERα), ER-beta (ERβ), or G protein-coupled ER (GPER)) through genomic or non-genomic pathways, which regulate cardiovascular function and prevent tissue remodeling. Despite the extensive knowledge on the cardioprotective effects of estrogen, clinical studies conducted on myocardial infarction (MI) and cardiovascular diseases still include favorable and unfavorable profiles. The purpose of this review is to provide up-to-date information regarding molecular, preclinical, and clinical aspects of cardiovascular E2 effects and ER modulation as a potential therapeutic target for the treatment of MI-induced cardiac dysfunction.
Background and Purpose
Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy and increased right ventricular systolic ...pressure. Here, we investigated the effects of a N‐acylhydrazone derivative, 3,4‐dimethoxyphenyl‐N‐methyl‐benzoylhydrazide (LASSBio‐1359), on monocrotaline (MCT)‐induced pulmonary hypertension in rats.
Experimental Approach
PAH was induced in male Wistar rats by a single i.p. injection of MCT (60 mg·kg−1) and 2 weeks later, oral LASSBio‐1359 (50 mg·kg−1) or vehicle was given once daily for 14 days. Echocardiography was used to measure cardiac function and pulmonary artery dimensions, with histological assay of vascular collagen. Studies of binding to human recombinant adenosine receptors (A1, A2A, A3) and of docking with A2A receptors were also performed.
Key Results
MCT administration induced changes in vascular and ventricular structure and function, characteristic of PAH. These changes were reversed by treatment with LASSBio‐1359. MCT also induced endothelial dysfunction in pulmonary artery, as measured by diminished relaxation of pre‐contracted arterial rings, and this dysfunction was reversed by LASSBio‐1359. In pulmonary artery rings from normal Wistar rats, LASSBio‐1359 induced relaxation, which was decreased by the adenosine A2A receptor antagonist, ZM 241385. In adenosine receptor binding studies, LASSBio‐1359 showed most affinity for the A2A receptor and in the docking analyses, binding modes of LASSBio‐1359 and the A2A receptor agonist, CGS21680, were very similar.
Conclusion and Implications
In rats with MCT‐induced PAH, structural and functional changes in heart and pulmonary artery were reversed by treatment with oral LASSBio‐1359, most probably through the activation of adenosine A2A receptors.
The mechanisms and antinociceptive effects of a novel α2A adrenoceptor agonist, 3-(2-chloro-6-fluorobenzil)-imidazolinide-2,4-dione (PT-31) were investigated using animal models of acute and chronic ...pain. The effects of PT-31 on pain responses were examined using hot plate and formalin tests in mice and spinal nerve ligation (SNL)-induced hyperalgesia in rats. The effects of antagonists acting on α adrenoceptor were assessed to investigate the interaction of these pathways upon PT-31 induced antinociception. PT-31 effects on motor activity/skills and on hemodynamic parameters were also evaluated. PT-31 had dose-dependent antinociception effects on hot-plate and formalin-injection induced pain responses. Thermal hyperalgesia and mechanical allodynia were reduced following a 7 d treatment with PT-31 (1, 5, and 10mg/kg/d, p.o.), and those effects were attenuated by yohimbine (5mg/kg), atropine (2mg/kg), L-nitro arginine methyl ester (L-NAME; 30mg/kg), or naloxone (2mg/kg). In contrast to clonidine, PT-31 did not have locomotor or hemodynamic effects in rats. The present results suggest that PT-31 represents a candidate for pain treatment with advantages over clonidine, namely no locomotor or hemodynamic impairments.
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