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Akhmedov A.T.,Molecular Cardiology and Neuromuscular Institute | Marin-Garcia J.,Molecular Cardiology and Neuromuscular Institute
Heart Failure Reviews | Year: 2013

Human heart failure (HF) is one of the leading causes of morbidity and mortality worldwide. Currently, heart transplantation and implantation of mechanical devices represent the only available treatments for advanced HF. Two alternative strategies have emerged to treat patients with HF. One approach relies on transplantation of exogenous stem cells (SCs) of non-cardiac or cardiac origin to induce cardiac regeneration and improve ventricular function. Another complementary strategy relies on stimulation of the endogenous regenerative capacity of uninjured cardiac progenitor cells to rebuild cardiac muscle and restore ventricular function. Various SC types and delivery strategies have been examined in the experimental and clinical settings; however, neither the ideal cell type nor the cell delivery method for cardiac cell therapy has yet emerged. Although the use of bone marrow (BM)-derived cells, most frequently exploited in clinical trials, appears to be safe, the results are controversial. Two recent randomized trials have failed to document any beneficial effects of intracardiac delivery of autologous BM mononuclear cells on cardiac function of patients with HF. The remarkable discovery that various populations of cardiac progenitor cells (CPCs) are present in the adult human heart and that it possesses limited regeneration capacity has opened a new era in cardiac repair. Importantly, unlike BM-derived SCs, autologous CPCs from myocardial biopsies cultured and subsequently delivered by coronary injection to patients have given positive results. Although these data are promising, a better understanding of how to control proliferation and differentiation of CPCs, to enhance their recruitment and survival, is required before CPCs become clinically applicable therapeutics. © 2012 Springer Science+Business Media, LLC. Source


Tan T.,Rutgers University | Tan T.,Johnson University | Marin-Garcia J.,Molecular Cardiology and Neuromuscular Institute | Damle S.,Molecular Cardiology and Neuromuscular Institute | Weiss H.R.,Johnson University
Experimental Physiology | Year: 2010

Ageing reduces the ability of cardiac myocytes to respond to inotropic agents. We hypothesized that hypoxia-inducible factor-1 (HIF-1) would improve the functional and Ca2+ transient responses of ageing myocytes to the inotropic agents and this would act, in part, through altered mitochondrial activity. Young (3-4 months) and older Fischer 344 rats (18-20 months) were used. Hypoxia-inducible factor-1α was upregulated with ciclopirox olamine (CPX, 50 mg kg-1 on 2 days). Hypoxia-inducible factor-1 upregulation was detected by Western blot. Cardiomyocyte contraction and Ca2+ transients were measured at baseline and after forskolin and ouabain. We also measured mitochondrial complex activities and production of reactive oxygen species (ROS). In the young group, forskolin (31%) and ouabain (31%) significantly increased percentage shortening. Similar changes were observed in the young + CPX group. Calcium transients also responded in a similar manner. However, in the older group, forskolin (12%) and ouabain (6%) did not significantly increase myocyte contractility or Ca2+ transients. In the older + CPX group, the effects of forskolin (34%) and ouabain (29%) were restored. In the young + CPX group, there was increased ROS production and mitochondrial complex I and III activity compared with the young group. These differences were not observed in older groups. These data demonstrate an impaired functional and Ca2+ effect of positive inotropic agents in older myocytes. Upregulation of HIF-1 restored this blunted response, but this was not related to changed mitochondrial activity induced by HIF-1. Thus, we found that HIF-1 improved inotropy in older myocytes without requiring mitochondrial activity changes. © 2010 The Physiological Society. Source


Damle S.,Molecular Cardiology and Neuromuscular Institute | Marin-Garcia J.,Molecular Cardiology and Neuromuscular Institute
Current Enzyme Inhibition | Year: 2010

Mitochondrial uncoupling proteins (UCPs), members of a family of mitochondrial anion carrier proteins (MACP), are nuclear-encoded transmembrane transporter proteins located in the mitochondrial inner membrane. UCP1, mainly expressed in brown adipose tissue (BAT), was the first to be discovered and is responsible for animal thermogenesis; UCP2, originally thought to play a role in nonshivering thermogenesis, obesity and diabetes, its main function appears to be in the control of mitochondria-derived reactive oxygen species (ROS). Another uncoupling protein homologue, the UCP3 is mainly expressed in skeletal muscle and brown adipose tissue and its gene is transcribed from tissue-specific promoters in humans but not in rodents. All the members of this protein family possess a common feature of shunting protons across the mitochondrial inner membrane and reduce ATP synthesis; however, this common mechanism of action is used to carry out different functions by the different UCPs. The distribution and abundance of UCPs are tissue specific, which is also reflected into the processes that these proteins are thought to be participating. UCPs other than UCP1 are involved in several biological processes such as fatty acid (FA) metabolism, insulin secretion, oxidative stress (OS), heart pathophysiology and macrophage activation. New discoveries are advancing our understanding of UCP's roles in cardiovascular physiology. © 2010. Source


Marin-Garcia J.,Molecular Cardiology and Neuromuscular Institute | Akhmedov A.T.,Molecular Cardiology and Neuromuscular Institute | Moe G.W.,Li Ka Shing Knowledge Institute
Heart Failure Reviews | Year: 2013

Over the past decade, mitochondria have emerged as critical integrators of energy production, generation of reactive oxygen species (ROS), multiple cell death, and signaling pathways in the constantly beating heart. Clarification of the molecular mechanisms, underlying mitochondrial ROS generation and ROS-induced cell death pathways, associated with cardiovascular diseases, by itself remains an important aim; more recently, mitochondrial dynamics has emerged as an important active mechanism to maintain normal mitochondria number and morphology, both are necessary to preserve cardiomyocytes integrity. The two opposing processes, division (fission) and fusion, determine the cell type-specific mitochondrial morphology, the intracellular distribution and activity. The tightly controlled balance between fusion and fission is of particular importance in the high energy demanding cells, such as cardiomyocytes, skeletal muscles, and neuronal cells. A shift toward fission will lead to mitochondrial fragmentation, observed in quiescent cells, while a shift toward fusion will result in the formation of large mitochondrial networks, found in metabolically active cardiomyocytes. Defects in mitochondrial dynamics have been associated with various human disorders, including heart failure, ischemia reperfusion injury, diabetes, and aging. Despite significant progress in our understanding of the molecular mechanisms of mitochondrial function in the heart, further focused research is needed to translate this knowledge into the development of new therapies for various ailments. © 2012 Springer Science+Business Media, LLC. Source


Marin-Garcia J.,Molecular Cardiology and Neuromuscular Institute | Damle S.,Molecular Cardiology and Neuromuscular Institute | Jugdutt B.I.,University of Alberta | Moe G.W.,Li Ka Shing Knowledge Institute
Molecular and Cellular Biochemistry | Year: 2012

Myocardial ischemia results in early and progressive damage to mitochondrial structure and function, but the molecular events leading to these changes have not been clearly established. We hypothesized that mitochondrial dysfunction and a coordinated expression of nuclear and mitochondrial genes occur in a time-dependent manner by relating the time courses of changes in parameters of mitochondrial bioenergetics after ischemia-reperfusion. Using a Langendorff rat heart model, mitochondrial bioenergetics and protein levels were assessed at different times of ischemia and ischemia/reperfusion. Mitochondrial and nuclear gene expression (super array analysis) and mitochondrial DNA levels were evaluated after late ischemia. Ischemia induced progressive and marked decreases in complex I, III, and V activities. Reperfusion (15, 30, and 60 min) after 45 min of ischemia had little further effect on enzyme activities or respiration. Super array analysis after 45 min ischemia revealed increased levels of the proteins with more pronounced increases in the corresponding mRNAs. Expression of mitochondrial and nuclear genes involved in oxidative phosphorylation increased after 45 min of ischemia but not after reperfusion. Myocardial ischemia induces mitochondrial dysfunction and differential but coordinated expression of nuclear and mitochondrial genes in a time-dependent manner. Our observations are pertinent to the search for molecular stimuli that generate mitochondrial defects and alter mitochondrial and nuclear transcriptional responses that may impact ischemic preconditioning and cardioprotection. © Springer Science+Business Media, LLC. 2012. Source

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