Mesenchymal Stem Cells for Cardiac Regeneration: Translation to Bedside Reality

Cardiovascular disease (CVD) is the leading cause of death worldwide. According to the World Health Organization (WHO), an estimate of 17.3 million people died from CVDs in 2008 and by 2030, the number of deaths is estimated to reach almost 23.6 million. Despite the development of a variety of treatment options, heart failure management has failed to inhibit myocardial scar formation and replace the lost cardiomyocyte mass with new functional contractile cells. This shortage is complicated by the limited ability of the heart for self-regeneration. Accordingly, novel management approaches have been introduced into the field of cardiovascular research, leading to the evolution of gene- and cell-based therapies. Stem cell-based therapy (aka, cardiomyoplasty) is a rapidly growing alternative for regenerating the damaged myocardium and attenuating ischemic heart disease. However, the optimal cell type to achieve this goal has not been established yet, even after a decade of cardiovascular stem cell research. Mesenchymal stem cells (MSCs) in particular have been extensively investigated as a potential therapeutic approach for cardiac regeneration, due to their distinctive characteristics. In this paper, we focus on the therapeutic applications of MSCs and their transition from the experimental benchside to the clinical bedside

Role of Oxidative Stress in Thyroid Hormone-Induced Cardiomyocyte Hypertrophy and Associated Cardiac Dysfunction: An Undisclosed Story

Cardiac hypertrophy is the most documented cardiomyopathy following hyperthyroidism in experimental animals. Thyroid hormone-induced cardiac hypertrophy is described as a relative ventricular hypertrophy that encompasses the whole heart and is linked with contractile abnormalities in both right and left ventricles. The increase in oxidative stress that takes place in experimental hyperthyroidism proposes that reactive oxygen species are key players in the cardiomyopathy frequently reported in this endocrine disorder. The goal of this review is to shed light on the effects of thyroid hormones on the development of oxidative stress in the heart along with the subsequent cellular and molecular changes. In particular, we will review the role of thyroid hormone-induced oxidative stress in the development of cardiomyocyte hypertrophy and associated cardiac dysfunction, as well as the potential effectiveness of antioxidant treatments in attenuating these hyperthyroidism-induced abnormalities in experimental animal models

Vascular hypertrophy-associated hypertension of profilin1 transgenic mouse model leads to functional remodeling of peripheral arteries

Increased mechanical stress/hypertension in the vessel wall triggers the hypertrophic signaling pathway, resulting in structural remodeling of vasculature. Vascular hypertrophy of resistance vessels leads to reduced compliance and elevation of blood pressure. We showed before that increased expression of profilin1 protein in the medial layer of the aorta induces stress fiber formation, triggering the hypertrophic signaling resulting in vascular hypertrophy and, ultimately, hypertension in older mice. Our hypothesis is that profilin1 induced vascular hypertrophy in resistance vessels, which led to elevation of blood pressure, both of which contributed to the modulation of vascular function. Our results showed significant increases in the expression of α1- and β1-integrins (280 ± 6.3 and 325 ± 7.4%, respectively) and the activation of the Rho/Rho-associated kinase (ROCK) II pathway (260 and 350%, respectively, P < 0.05) in profilin1 mesenteric arteries. The activation of Rho/ROCK led to the inhibition of endothelial nitric oxide synthase expression (39 ± 5.4%; P < 0.05) and phosphorylation (35 ± 4.5%; P < 0.05) but also an increase in myosin light chain 20 phosphorylation (372%, P < 0.05). There were also increases in hypertrophic signaling pathways in the mesenteric arteries of profilin1 mice such as phospho-extracellular signal-regulated kinase 1/2 and phospho-c-Jun NH2-terminal kinase (312.15 and 232.5%, respectively, P < 0.05). Functional analyses of mesenteric arteries toward the vasoactive drugs were assessed using wire-myograph and showed significant increases in the vascular responses of profilin1 mesenteric arteries toward phenylephrine, but significant decreases in response toward ROCK inhibitor Y-27632, ACh, sodium nitrite, and cytochalasin D. The changes in vascular responses in the mesenteric arteries of profilin1 mice are due to vascular hypertrophy and the elevation of blood pressure in the profilin1 transgenic mice

Physiological Modification of the Contractile Force of Isolated Right Ventricular Papillary Muscles.

<p><b>(A) Frequency-dependent activation</b>; Isometric developed force values are expressed as a fraction of its corresponding value at the basal frequency of 4 Hz and presented as mean ± SEM, and (<b>B</b>) <b>β–adrenergic stimulation</b>; Isometric developed force values are expressed as a fraction of its corresponding value at the basal frequency of 4 Hz before isoproterenol addition and presented as mean ± SEM. Control; n = 12, Thyroxin (T4); n = 15, Dimethyl sulfoxide (DMSO); N = 10, Sorafenib; n = 9, Tadalafil_IP (intraperitoneal, 1 mg/kg); n = 10, Tadalafil_Or (oral, 4 mg/kg); n = 8, carboxymethylcellulose (CMC); n = 8, Macitentan_LD (Low dose: 30 mg/kg); n = 8, Macitentan_HD (High dose: 100 mg/kg); n = 7. Note: in the β–adrenergic stimulation curve (<b>B</b>), all isometric developed force values at which the muscles exhibited an arrhythmic behavior were excluded from the analysis. For example, the Macitentan_HD group has no representative point at isoproterenol concentration of 1 μM, because all muscles became arrhythmic at this concentration [i.e. 7 out of 7 (100%)]. (<b>C</b>) <b>Development of Arrhythmia</b>: % of arrhythmic muscles at different isoproterenol (Iso) concentrations. The absence of the representative bar of any group at any Iso concentration on the curve means the absence of arrhythmia at this concentration. *: indicates a significant change as revealed by one-way ANOVA followed by Dunnett Multiple Comparisons post-hoc test, comparing all groups to T4. +: indicates a significant change as revealed by two-way ANOVA.</p

The Effect of Sorafenib, Tadalafil and Macitentan Treatments on Thyroxin-Induced Hemodynamic Changes and Cardiac Abnormalities

<div><p>Multikinase inhibitors (e.g. Sorafenib), phosphodiesterase-5 inhibitors (e.g. Tadalafil), and endothelin-1 receptor blockers (e.g. Macitentan) exert influential protection in a variety of animal models of cardiomyopathy; however, their effects on thyroxin-induced cardiomyopathy have never been investigated. The goal of the present study was to assess the functional impact of these drugs on thyroxin-induced hemodynamic changes, cardiac hypertrophy and associated altered responses of the contractile myocardium both <i>in-vivo</i> at the whole heart level and <i>ex-vivo</i> at the cardiac tissue level. Control and thyroxin (500 μg/kg/day)-treated mice with or without 2-week treatments of sorafenib (10 mg/kg/day; I.P), tadalafil (1 mg/kg/day; I.P or 4 mg/kg/day; oral), macitentan (30 and 100 mg/kg/day; oral), and their vehicles were studied. Blood pressure, echocardiography and electrocardiogram were non-invasively evaluated, followed by <i>ex-vivo</i> assessments of isolated multicellular cardiac preparations. Thyroxin increased blood pressure, resulted in cardiac hypertrophy and left ventricular dysfunction <i>in-vivo</i>. Also, it caused contractile abnormalities in right ventricular papillary muscles <i>ex-vivo</i>. None of the drug treatments were able to significantly attenuate theses hemodynamic changes or cardiac abnormalities in thyroxin-treated mice. We show here for the first time that multikinase (raf1/b, VEGFR, PDGFR), phosphodiesterase-5, and endothelin-1 pathways have no major role in thyroxin-induced hemodynamic changes and cardiac abnormalities. In particular, our data show that the involvement of endothelin-1 pathway in thyroxine-induced cardiac hypertrophy/dysfunction seems to be model-dependent and should be carefully interpreted.</p></div

Rac-Induced Left Ventricular Dilation in Thyroxin-Treated ZmRacD Transgenic Mice: Role of Cardiomyocyte Apoptosis and Myocardial Fibrosis

<div><p>The pathways inducing the critical transition from compensated hypertrophy to cardiac dilation and failure remain poorly understood. The goal of our study is to determine the role of Rac-induced signaling in this transition process. Our previous results showed that Thyroxin (T4) treatment resulted in increased myocardial Rac expression in wild-type mice and a higher level of expression in Zea maize RacD (ZmRacD) transgenic mice. Our current results showed that T4 treatment induced physiologic cardiac hypertrophy in wild-type mice, as demonstrated by echocardiography and histopathology analyses. This was associated with significant increases in myocardial Rac-GTP, superoxide and ERK1/2 activities. Conversely, echocardiography and histopathology analyses showed that T4 treatment induced dilated cardiomyopathy along with compensatory cardiac hypertrophy in ZmRacD mice. These were linked with further increases in myocardial Rac-GTP, superoxide and ERK1/2 activities. Additionally, there were significant increases in caspase-8 expression and caspase-3 activity. However, there was a significant decrease in p38-MAPK activity. Interestingly, inhibition of myocardial Rac-GTP activity and superoxide generation with pravastatin and carvedilol, respectively, attenuated all functional, structural, and molecular changes associated with the T4-induced cardiomyopathy in ZmRacD mice except the compensatory cardiac hypertrophy. Taken together, T4-induced ZmRacD is a novel mouse model of dilated cardiomyopathy that shares many characteristics with the human disease phenotype. To our knowledge, this is the first study to show graded Rac-mediated O₂·⁻ results in cardiac phenotype shift <em>in-vivo</em>. Moreover, Rac-mediated O₂·⁻ generation, cardiomyocyte apoptosis, and myocardial fibrosis seem to play a pivotal role in the transition from cardiac hypertrophy to cardiac dilation and failure. Targeting Rac signaling could represent valuable therapeutic strategy not only in saving the failing myocardium but also to prevent this transition process.</p> </div