Abstract 61: Ablation of BK Ca Channels Results in Cardiac Hypertrophy

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Harpreet Singh ◽  
Kajol Shah ◽  
Devsena Ponnalagu ◽  
Sanjay Chandrasekhar ◽  
Andrew R Kohut ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Structural Changes ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Interventricular Septum ◽  
Wild Type

Expression and activation of the large conductance calcium and voltage-gated potassium (BK Ca ) channels encoded by Kcnma1 gene is shown to be vital in cardioprotection from ischemia-reperfusion injury. BK Ca channels present in SA node cells regulate the heart rate, and in blood vessels play an active role in vascular relaxation. However, the role of BK Ca in regulation of structure and function of the heart is not fully-established. Using Kcnma1 -/- mice, we have observed structural changes in cardiomyocytes and compromised cardiac function as compared to wild type mice. Absence of BK Ca resulted in significant increase in size of adult cardiomyocytes (from 7.95 + 0.1 um 2 to 9.68 + 0.1 um 2 , p < 0.01, n=480 cells each) and also increased cardiac fibrosis. Further to determine underlying signaling mechanisms in cardiac hypertrophy, we performed microarray analysis of RNAs isolated from wild type and Kcnma1 -/- mice (n=3) hearts. We found up regulation of a class of cardiac hypertrophy markers (myosin variants) and changes in the expression of several mitochondrial genes (such as ND4) directly associated with heart diseases in Kcnma1 -/- mice. To evaluate the functional consequence of absence of BK Ca , we performed high-resolution echocardiography on wild type and Kcnma1 -/- mice. Under anesthesia (1.5% isoflurane), left ventricle of Kcnma1 -/- mice showed significant reduction (p < 0.05) in ejection fraction (56 + 2 %, n=7) as compared to wild type (74 + 3 %, n=6) as well as fractional shortening (23 + 3 %, n=7, and 39 + 3 %, n=6, respectively). Similarly, right ventricle had a lower ejection fraction (35.7 + 4% vs 56.9 + 5 %, n > 5) in Kcnma1 -/- as compared to wild type mice. In agreement with our histopathology and microarray data, Kcnma1 -/- mice showed increased posterior wall thickness (0.75 + 0.3 mm vs 0.62 + 0.1 mm) and interventricular septum thickness (0.83 + 0.4 mm, n=7 vs 0.68 + 0.3 mm, n=6) . Together, these data imply that BK Ca plays a direct role in cardiac hypertrophy and cardiac function.

scholarly journals The roles of long noncoding RNAs in myocardial pathophysiology

2019 ◽  
Vol 39 (11) ◽  
Author(s):  
Cheng Chen ◽  
Yuting Tang ◽  
Hui Sun ◽  
Xiaofang Lin ◽  
Bimei Jiang
Keyword(s):  
Structural Changes ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Current Knowledge ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Noncoding Rnas ◽  
Cardiac Cells ◽  
Long Noncoding Rnas ◽  
Ischemic Heart

Abstract Long noncoding RNAs (lncRNAs), more than 200 nt in length, are functional molecules found in various species. These lncRNAs play a vital role in cell proliferation, differentiation, and degeneration and are also involved in pathophysiological processes of cancer and neurodegenerative, autoimmune, and cardiovascular diseases (CVDs). In recent years, emerging challenges for intervention studies on ischemic heart diseases have received much attention. LncRNAs have a key function in the alleviation of myocardial infarction (MI) injury and myocardial ischemia–reperfusion injury. During cardiac hypertrophy (CH) and fibrosis, cardiac cells undergo structural changes and become dysfunctional due to the effects of neurohormonal factors. LncRNAs may serve as important therapeutic targets that promote cardiac remodeling and then retard the development of heart failure (HF). In addition, studies on the roles and mechanisms of action of lncRNAs participating in cardiac pathophysiology via other factors have become the focus of research worldwide. Here, we review the current knowledge on various lncRNAs and their functions in cardiac biology, particularly concentrating on ischemic heart disease, CH, and cardiac fibrosis. We next discuss the predictive value of lncRNAs as diagnostic biomarkers of CVDs.

Abstract 409: Matrix Metalloproteinase-13 Inhibition is Protective in a Pressure Overload Model of Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Allison E Schafer ◽  
Iñigo Valiente-Alandi ◽  
Burns C Blaxall
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Proteolytic Enzymes ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
The United States ◽  
Cardiac Cells ◽  
Ecm Proteins

Heart failure (HF), the leading cause of morbidity and mortality in the United States, is characterized by pathologic remodeling, fibrosis and deteriorating cardiac function. Cardiac fibrosis occurs due to imbalanced production and degradation of extracellular matrix (ECM) proteins. Cardiac fibroblasts (CF) are largely responsible for the secretion of ECM proteins in the heart, and upon injury, transition to a migratory and proliferative myofibroblast (MF) phenotype, leading to excess ECM deposition. Elevated expression of matrix metalloproteinases (MMPs), proteolytic enzymes responsible for degradation of the ECM, is common in HF. Specifically, MMP13 is known to be upregulated in human HF patients. Therefore, we hypothesized that MMP13 plays an important role in pathologic cardiac remodeling, and that inhibition of MMP13 would prevent the development of HF in a pressure overload model, transverse aortic constriction (TAC). Mice were subjected to TAC and treated with the MMP13 inhibitor, WAY170523 (WAY), or vehicle 4 weeks post-TAC until 12 weeks post-TAC. Mice treated with WAY display decreased cardiac hypertrophy and preserved cardiac function compared to vehicle treated mice. WAY treatment may also attenuate interstitial and perivascular fibrosis as well as expression of pro-fibrotic genes. To determine the effect of MMP13 inhibition in cardiac cells, CF and MF were isolated from healthy mice or mice 5 days post-ischemia/reperfusion injury, respectively, and treated with WAY. MMP13 inhibition led to decreased CF invasion but did not affect migration, proliferation or adhesion. Interestingly, inhibition of MMP13 in MF attenuated migration, proliferation and invasion. Moreover, WAY treatment reduced collagen and fibronectin deposition in the ECM of MF. MMP13 inhibition also appeared to decrease Angiotensin II-induced hypertrophy in ventricular cardiomyocytes (CM). These data suggest a role for MMP13 in pressure overload-induced HF, CM hypertrophy and CF behavior. MMP13 inhibition after injury may attenuate cardiac hypertrophy as well as the CF to MF transition, leading to decreased cardiac fibrosis and improved cardiac function. Further understanding of the role of MMP13 could lead to a novel therapeutic target in the treatment of HF.

scholarly journals Gypenoside Protects against Myocardial Ischemia-Reperfusion Injury by Inhibiting Cardiomyocytes Apoptosis via Inhibition of CHOP Pathway and Activation of PI3K/Akt Pathway In Vivo and In Vitro

2016 ◽  
Vol 39 (1) ◽  
pp. 123-136 ◽  
Author(s):  
Haijie Yu ◽  
Haishan Zhang ◽  
Weihua Zhao ◽  
Liang Guo ◽  
Xueyuan Li ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Er Stress ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Akt Pathway ◽  
Cardiac Structure ◽  
Cell Models

Background/Aims: Ischemia-reperfusion (I/R) injury is believed to be the major cause for detriments in coronary heart diseases, but few effective therapies for prevention or treatment of I/R injury are available. Gypenoside (GP) is the predominant effective component of Gynostemma pentaphyllum and possesses capacities against inflammation and oxidation. In the present study, the role of GP in ameliorating myocardial I/R injury was investigated. Methods: effect GP on the cardiac structure of I/R injured rats was assessed by H&amp;E and TTC staining. Then the influence of GP on the cardiac function of rat model was determined by measuring hemodynamics parameters, levels of lactate dehydrogenase (LDH) and creatine kinase (CK). Thereafter, effect of GP on apoptotic process was evaluated with both rat and cell models. The production of molecules related to ER stress and apoptosis was quantified for revelation of pathways involved in the myocardial protective effect of GP. Results: Impairments in cardiac structure due to I/R injury was ameliorated by GP treatment. And it was evidently demonstrated that administration of GP not only effectively decreased the apoptotic rates in both rat and cell models but also markedly improved the cardiac function of I/R injured rats. In addition, results of western blotting revealed that the GP inhibited ER-stress and apoptosis through the blockade of CHOP pathway and activation of PI3K/Akt pathway. Conclusion: the current study showed the potential of GP to alleviate myocardial I/R injury and preliminarily uncovered the underling mechanism driving this treatment.

scholarly journals Role of Higenamine in Heart Diseases: A Mini-Review

2022 ◽  
Vol 12 ◽  
Author(s):  
Jianxia Wen ◽  
Mingjie Li ◽  
Wenwen Zhang ◽  
Haoyu Wang ◽  
Yan Bai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Heart Disease ◽  
Reperfusion Injury ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia

Higenamine, a natural product with multiple targets in heart diseases, is originally derived from Aconitum, which has been traditionally used in China for the treatment of heart disease, including heart failure, arrhythmia, bradycardia, cardiac ischemia/reperfusion injury, cardiac fibrosis, etc. This study is aimed to clarify the role of higenamine in heart diseases. Higenamine has effects on improving energy metabolism of cardiomyocytes, anti-cardiac fibroblast activation, anti-oxidative stress and anti-apoptosis. Accumulating evidence from various studies has shown that higenamine exerts a wide range of cardiovascular pharmacological effects in vivo and in vitro, including alleviating heart failure, reducing cardiac ischemia/reperfusion injury, attenuating pathological cardiac fibrosis and dysfunction. In addition, several clinical studies have reported that higenamine could continuously increase the heart rate levels of healthy volunteers as well as patients with heart disease, but there are variable effects on systolic blood pressure and diastolic blood pressure. Moreover, the heart protection and therapeutic effects of higenamine on heart disease are related to regulating LKB1/AMPKα/Sirt1, mediating the β2-AR/PI3K/AKT cascade, induction of heme oxygenase-1, suppressing TGF-β1/Smad signaling, and targeting ASK1/MAPK (ERK, P38)/NF-kB signaling pathway. However, the interventional effects of higenamine on heart disease and its underlying mechanisms based on experimental studies have not yet been systematically reviewed. This paper reviewed the potential pharmacological mechanisms of higenamine on the prevention, treatment, and diagnosis of heart disease and clarified its clinical applications. The literature shows that higenamine may have a potent effect on complex heart diseases, and proves the profound medicinal value of higenamine in heart disease.

scholarly journals Prostaglandin E Receptor Subtype 4 Signaling in the Heart: Role in Ischemia/Reperfusion Injury and Cardiac Hypertrophy

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Lei Pang ◽  
Yin Cai ◽  
Eva Hoi Ching Tang ◽  
Michael G. Irwin ◽  
Haichun Ma ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Ischemic Heart ◽  
Prostaglandin E ◽  
Ischemic Heart Diseases ◽  
Ep4 Receptor ◽  
Arachidonic Acids

Prostaglandin E2(PGE2) is an endogenous lipid mediator, produced from the metabolism of arachidonic acids, upon the sequential actions of phospholipase A2, cyclooxygenases, and prostaglandin E synthases. The various biological functions governed by PGE2are mediated through its four distinct prostaglandin E receptors (EPs), designated as EP1, EP2, EP3, and EP4, among which the EP4 receptor is the one most widely distributed in the heart. The availability of global or cardiac-specific EP4 knockout mice and the development of selective EP4 agonists/antagonists have provided substantial evidence to support the role of EP4 receptor in the heart. However, like any good drama, activation of PGE2-EP4 signaling exerts both protective and detrimental effects in the ischemic heart disease. Thus, the primary object of this review is to provide a comprehensive overview of the current progress of the PGE2-EP4 signaling in ischemic heart diseases, including cardiac hypertrophy and myocardial ischemia/reperfusion injury. A better understanding of PGE2-EP4 signaling should promote the development of more effective therapeutic approaches to treat the ischemic heart diseases without triggering unwanted side effects.

Breathing nitric oxide plus hydrogen gas reduces ischemia-reperfusion injury and nitrotyrosine production in murine heart

2013 ◽  
Vol 305 (4) ◽  
pp. H542-H550 ◽  
Author(s):  
Toshihiro Shinbo ◽  
Kenichi Kokubo ◽  
Yuri Sato ◽  
Shintaro Hagiri ◽  
Ryuji Hataishi ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Function ◽  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Neutrophil Infiltration ◽  
Left Ventricular ◽  
Hydrogen Gas ◽  
Coronary Artery Ligation

Inhaled nitric oxide (NO) has been reported to decrease the infarct size in cardiac ischemia-reperfusion (I/R) injury. However, reactive nitrogen species (RNS) produced by NO cause myocardial dysfunction and injury. Because H2 is reported to eliminate peroxynitrite, it was expected to reduce the adverse effects of NO. In mice, left anterior descending coronary artery ligation for 60 min followed by reperfusion was performed with inhaled NO [80 parts per million (ppm)], H2 (2%), or NO + H2, starting 5 min before reperfusion for 35 min. After 24 h, left ventricular function, infarct size, and area at risk (AAR) were assessed. Oxidative stress associated with reactive oxygen species (ROS) was evaluated by staining for 8-hydroxy-2′-deoxyguanosine and 4-hydroxy-2-nonenal, that associated with RNS by staining for nitrotyrosine, and neutrophil infiltration by staining for granulocyte receptor-1. The infarct size/AAR decreased with breathing NO or H2 alone. NO inhalation plus H2 reduced the infarct size/AAR, with significant interaction between the two, reducing ROS and neutrophil infiltration, and improved the cardiac function to normal levels. Although nitrotyrosine staining was prominent after NO inhalation alone, it was eliminated after breathing a mixture of H2 with NO. Preconditioning with NO significantly reduced the infarct size/AAR, but not preconditioning with H2. In conclusion, breathing NO + H2 during I/R reduced the infarct size and maintained cardiac function, and reduced the generation of myocardial nitrotyrosine associated with NO inhalation. Administration of NO + H2 gases for inhalation may be useful for planned coronary interventions or for the treatment of I/R injury.

scholarly journals Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia

2008 ◽  
Vol 294 (6) ◽  
pp. H2889-H2897 ◽  
Author(s):  
Qianwen Wang ◽  
Rajakumar V. Donthi ◽  
Jianxun Wang ◽  
Alex J. Lange ◽  
Lewis J. Watson ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Fibrosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Weight Ratio ◽  
Cardiac Metabolism ◽  
Heart Weight ◽  
Acid Oxidation ◽  
Important Regulator

During ischemia and heart failure, there is an increase in cardiac glycolysis. To understand if this is beneficial or detrimental to the heart, we chronically elevated glycolysis by cardiac-specific overexpression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) in transgenic mice. PFK-2 controls the level of fructose-2,6-bisphosphate (Fru-2,6-P2), an important regulator of phosphofructokinase and glycolysis. Transgenic mice had over a threefold elevation in levels of Fru-2,6-P2. Cardiac metabolites upstream of phosphofructokinase were significantly reduced, as would be expected by the activation of phosphofructokinase. In perfused hearts, the transgene caused a significant increase in glycolysis that was less sensitive to inhibition by palmitate. Conversely, oxidation of palmitate was reduced by close to 50%. The elevation in glycolysis made isolated cardiomyocytes highly resistant to contractile inhibition by hypoxia, but in vivo the transgene had no effect on ischemia-reperfusion injury. Transgenic hearts exhibited pathology: the heart weight-to-body weight ratio was increased 17%, cardiomyocyte length was greater, and cardiac fibrosis was increased. However, the transgene did not change insulin sensitivity. These results show that the elevation in glycolysis provides acute benefits against hypoxia, but the chronic increase in glycolysis or reduction in fatty acid oxidation interferes with normal cardiac metabolism, which may be detrimental to the heart.

Abstract 428: Pharmacologic and Activated Fibroblast-specific Gβγ-GRK2 Inhibition is Protective Following Ischemia Reperfusion Injury

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Joshua G Travers ◽  
Fadia A Kamal ◽  
Michelle L Nieman ◽  
Michelle A Sargent ◽  
Jeffery D Molkentin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Reperfusion Injury ◽  
G Protein ◽  
Knockout Mice ◽  
Ischemia Reperfusion Injury ◽  
Interstitial Fibrosis ◽  
Myocardial Dysfunction ◽  
Ischemia Reperfusion ◽  
Ventricular Compliance

Heart failure is a devastating disease characterized by chamber remodeling, interstitial fibrosis and reduced ventricular compliance. Cardiac fibroblasts are responsible for extracellular matrix homeostasis, however upon injury or pathologic stimulation, these cells transform to a myofibroblast phenotype and play a fundamental role in myocardial fibrosis and remodeling. Chronic sympathetic overstimulation induces excess signaling through G protein βγ subunits and ultimately the pathologic activation of G protein-coupled receptor kinase 2 (GRK2). We hypothesized that Gβγ-GRK2 inhibition plays an important role in the cardiac fibroblast to attenuate pathologic myofibroblast activation and cardiac remodeling. To investigate this hypothesis, mice were subjected to ischemia/reperfusion (I/R) injury and treated with the small molecule Gβγ-GRK2 inhibitor gallein. While animals receiving vehicle demonstrated a reduction in overall cardiac function as measured by echocardiography, mice treated with gallein exhibited nearly complete preservation of cardiac function and reduced fibrotic scar formation. We next sought to establish the cell specificity of this compound by treating inducible cardiomyocyte- and activated fibroblast-specific GRK2 knockout mice post-I/R. Although we observed modest restoration in cardiac function in cardiomyocyte-specific GRK2 null mice, treatment of these mice with gallein resulted in further protection against myocardial dysfunction following injury, suggesting a functional role in other cardiac cell types, including fibroblasts. Activated fibroblast-specific GRK2 knockout mice were also subjected to ischemia/reperfusion injury; these animals displayed preserved myocardial function and reduced collagen deposition compared to littermate controls following injury. Furthermore, systemic Gβγ-GRK2 inhibition by gallein did not appear to confer further protection over activated fibroblast-specific GRK2 ablation alone. In summary, these findings suggest a potential therapeutic role for Gβγ-GRK2 inhibition in limiting pathologic myofibroblast activation, interstitial fibrosis and heart failure progression.

Abstract 47: Loss of the Cardio Protection Inferred by S-nitrosylation of GRK2 At Cysteine 340 Leads to Decreased Cardiac Performance and a Hypertensive Phenotype With Aging

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Christopher J Traynham ◽  
Ancai Yuan ◽  
Erhe Gao ◽  
Walter Koch
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Ischemia Reperfusion ◽  
Cardiac Performance ◽  
Heart Weight ◽  
Cardiac Phenotype ◽  
Cardio Protection ◽  
G Protein Coupled ◽  
Global Population

In the next 35 years, the global population of individuals above 60 years of age will double to approximately 2 billion. In the aged population, cardiovascular diseases are known to occur at a higher prevalence ultimately leading to increased mortality. G protein-coupled receptors (GPCRs) have been identified as vital regulators of cardiac function. GPCR kinases (GRKs) are important in cardiac GPCR regulation through desensitization of these receptors. GRK2 is highly expressed in the heart, and has been widely characterized due to its upregulation in heart failure. Studies from our lab have shown that elevated GRK2 levels in ischemia-reperfusion (I/R) injury result in a pro-death phenotype. Interestingly, cardio-protection can be inferred via S-nitrosylation of GRK2 at cysteine 340. Further, we have generated a knock-in GRK2 340S mouse, in which cysteine 340 was mutated to block dynamic GRK2 S-nitrosylation. GRK2 340S mice are more susceptible to I/R injury. Given that GRK2 340S mice are more susceptible to oxidative stress, and there is a nitroso-redox imbalance in senescence, it is possible that these mice are more likely to exhibit decreased cardiac performance as they age. Therefore, we hypothesize that with age GRK2 340S knockin mice will develop an overall worsened cardiac phenotype compared to control wild-type (WT) mice. To test this hypothesis, 340S and WT mice were aged for a year, and cardiac function was evaluated via echocardiography. Aged 340S mice exhibited significantly decreased ejection fraction and fraction shortening relative to aged WT controls. Prior to tissue harvesting, in-vivo hemodynamics was conducted via Millar catheterization. At baseline, aged 340S mice exhibited increased systolic blood pressure compared to aged WT mice. At the conclusion of this protocol, mice were sacrificed and heart weight (HW), body weight (BW), and tibia length (TL) measured to evaluate cardiac hypertrophy. Aged 340S mice exhibited significantly increased HW/BW and HW/TL ratios, indicative of cardiac hypertrophy, relative to aged WT controls. Taken together, these data suggest that with age, loss of the cardio protection inferred by S-nitrosylation of GRK2 at leads to decreased cardiac performance, and an overall worsened cardiac phenotype.

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