scholarly journals Conditional increase in SERCA2a protein is able to reverse contractile dysfunction and abnormal calcium flux in established diabetic cardiomyopathy

2008 ◽  
Vol 295 (5) ◽  
pp. R1439-R1445 ◽  
Author(s):  
Jorge Suarez ◽  
Brian Scott ◽  
Wolfgang H. Dillmann
Keyword(s):  
Cardiac Function ◽  
Diabetic Cardiomyopathy ◽  
Cardiac Contractility ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Calcium Flux ◽  
Calcium Handling ◽  
Contractile Dysfunction ◽  
Diabetic Mice ◽  
Perfused Heart

Diabetic cardiomyopathy is characterized by reduced cardiac contractility independent of vascular disease. A contributor to contractile dysfunction in the diabetic heart is impaired sarcoplasmic reticulum function with reduced sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) pump activity, leading to disturbed intracellular calcium handling. It is currently unclear whether increasing SERCA2a activity in hearts with existing diabetic cardiomyopathy could still improve calcium flux and contractile performance. To test this hypothesis, we generated a cardiac-specific tetracycline-inducible double transgenic mouse, which allows for doxycycline (DOX)-based inducible SERCA2a expression in which DOX exposure turns on SERCA2a expression. Isolated cardiomyocytes and Langendorff perfused hearts from streptozotocin-induced diabetic mice were studied. Our results show that total SERCA2a protein levels were decreased in the diabetic mice by 60% compared with control. SERCA2a increased above control values in the diabetic mice after DOX. Dysfunctional contractility in the diabetic cardiomyocyte was restored to normal by induction of SERCA2a expression. Calcium transients from diabetic cardiomyocytes showed a delayed rate of diastolic calcium decay of 66%, which was reverted toward normal after SERCA2a expression induced by DOX. Global cardiac function assessed in the diabetic perfused heart showed diminished left ventricular pressure, rate of contraction, and relaxation. These parameters were returned to control values by SERCA2a expression. In conclusion, we have used mice allowing for inducible expression of SERCA2a and could demonstrate that increased expression of SERCA2a leads to improved cardiac function in mice with an already established diabetic cardiomyopathy in absence of detrimental effects.

Muscle metabolism and cardiac function of the myopathic hamster following training

1977 ◽  
Vol 43 (6) ◽  
pp. 936-941 ◽  
Author(s):  
W. L. Sembrowich ◽  
M. B. Knudson ◽  
P. D. Gollnick
Keyword(s):  
Skeletal Muscle ◽  
Cardiac Function ◽  
Myocardial Function ◽  
Cardiac Contractility ◽  
Muscle Metabolism ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Treadmill Running ◽  
Succinate Dehydrogenase Activity ◽  
Positive Effect

The effect of 18 wk of treadmill running on skeletal muscle metabolism and myocardial function of normal and myopathic hamsters was examined. BIO 14.6 hamsters could tolerate an exercise intensity of about 18 m/min for 40 min, 5 days/wk. Further increases in speed or number of bouts per day resulted in a falloff in performance. Normal hamsters could tolerate higher speeds and longer exercise bouts. Exercise did not change the severity of lesions of either the heart or skeletal muscle of the myopathic hamsters. A training effect was evidenced by increased succinate dehydrogenase activity in the soleus muscle. Cardiac function was evaluated as contractility measured from left ventricular pressure curves and expressed as (dP/dt)/kP. The results suggested that cardiac contractility was not as severely depressed in the trained BIO 14.6 strain of hamsters as in nontrained controls. However, (dP/dt)/kP was lower in the trained myopathic animals than in normal hamsters. ATP, CP, and glycogen levels were lower in myopathic hamsters with the lowest values occurring in the trained group. These data demonstrate that the BIO 14.6 strain of hamster can tolerate exercise training and that such training may have a positive effect on cardiac function.

Molecular and pharmacological approaches to inhibiting nitric oxide after burn trauma

2003 ◽  
Vol 285 (4) ◽  
pp. H1616-H1625 ◽  
Author(s):  
Jean White ◽  
Deborah L. Carlson ◽  
Marita Thompson ◽  
David L. Maass ◽  
Billy Sanders ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Function ◽  
Total Body Surface Area ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Contractile Dysfunction ◽  
Wild Type ◽  
Burn Trauma ◽  
Cardiac Contractile ◽  
Cardiac Contractile Dysfunction

Whereas controversial, several studies have suggested that nitric oxide (NO) alters cardiac contractility via cGMP, peroxynitrite, or poly(ADP ribose) synthetase (PARS) activation. This study determined whether burn-related upregulation of myocardial inducible NO synthase (iNOS) and NO generation contributes to burn-mediated cardiac contractile dysfunction. Mice homozygous null for the iNOS gene (iNOS knockouts) were obtained from Jackson Laboratory. iNOS knockouts (KO) as well as wild-type mice were given a cutaneous burn over 40% of the total body surface area by the application of brass probes (1 × 2 × 0.3 cm) heated to 100°C to the animals' sides and back for 5 s (iNOS/KO burn and wild-type burn). Additional groups of iNOS KO and wild-type mice served as appropriate sham burn groups (iNOS/KO sham and wild-type sham). Cardiac function was assessed 24 h postburn by perfusing hearts ( n = 7–10 mice/group). Burn trauma in wild-type mice impaired cardiac function as indicated by the lower left ventricular pressure (LVP, 67 ± 2 mmHg) compared with that measured in wild-type shams (94 ± 2 mmHg, P < 0.001), a lower rate of LVP rise (+dP/d tmax, 1,620 ± 94 vs. 2,240 ± 58 mmHg/s, P < 0.001), and a lower rate of LVP fall (–dP/d tmax, 1,200 ± 84 vs. 1,800 ± 42 mmHg/s, P < 0.001). Ventricular function curves confirmed significant contractile dysfunction after burn trauma in wild-type mice. Burn trauma in iNOS KO mice produced fewer cardiac derangements compared with those observed in wild-type burns (LVP: 78 ± 5 mmHg; +dP/d t: 1,889 ± 160 mmHg/s; –dP/d t: 1,480 ± 154 mmHg/s). The use of a pharmacological approach to inhibit iNOS (aminoguanidine, given ip) in additional wild-type shams and burns confirmed the iNOS KO data. Whereas the absence of iNOS attenuated burn-mediated cardiac contractile dysfunction, these experiments did not determine the contribution of cardiac-derived NO versus NO generated by immune cells. However, our data indicate a role for NO in cardiac dysfunction after major trauma.

scholarly journals Excess protein O-GlcNAcylation and the progression of diabetic cardiomyopathy

2012 ◽  
Vol 303 (7) ◽  
pp. R689-R699 ◽  
Author(s):  
Eduardo S. Fricovsky ◽  
Jorge Suarez ◽  
Sang-Hyun Ihm ◽  
Brian T. Scott ◽  
Jorge A. Suarez-Ramirez ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Cardiac Function ◽  
Diastolic Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Time Course ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Fasting Blood Glucose ◽  
Left Ventricular ◽  
Calcium Handling

We examined the role that enzymatic protein O-GlcNAcylation plays in the development of diabetic cardiomyopathy in a mouse model of Type 2 diabetes mellitus (DM2). Mice injected with low-dose streptozotocin and fed a high-fat diet developed mild hyperglycemia and obesity consistent with DM2. Studies were performed from 1 to 6 mo after initiating the DM2 protocol. After 1 mo, DM2 mice showed increased body weight, impaired fasting blood glucose, and hyperinsulinemia. Echocardiographic evaluation revealed left ventricular diastolic dysfunction by 2 mo and O-GlcNAcylation of several cardiac proteins and of nuclear transcription factor Sp1. By 4 mo, systolic dysfunction was observed and sarcoplasmic reticulum Ca2+ ATPase expression decreased by 50%. Fibrosis was not observed at any timepoint in DM2 mice. Levels of the rate-limiting enzyme of the hexosamine biosynthetic pathway, glutamine:fructose-6-phosphate amidotransferase (GFAT) were increased as early as 2 mo. Fatty acids, which are elevated in DM2 mice, can possibly be linked to excessive protein O-GlcNAcylation levels, as cultured cardiac myocytes in normal glucose treated with oleic acid showed increased O-GlcNAcylation and GFAT levels. These data indicate that the early onset of diastolic dysfunction followed by the loss of systolic function, in the absence of cardiac hypertrophy or fibrosis, is associated with increased cardiac protein O-GlcNAcylation and increased O-GlcNAcylation levels of key calcium-handling proteins. A link between excessive protein O-GlcNAcylation and cardiac dysfunction is further supported by results showing that reducing O-GlcNAcylation by O-GlcNAcase overexpression improved cardiac function in the diabetic mouse. In addition, fatty acids play a role in stimulating excess O-GlcNAcylation. The nature and time course of changes observed in cardiac function suggest that protein O-GlcNAcylation plays a mechanistic role in the triggering of diabetic cardiomyopathy in DM2.

The Effect of Gypenosides on Cardiac Function and Expression of Cytoskeletal Genes of Myocardium in Diabetic Cardiomyopathy Rats

2009 ◽  
Vol 37 (06) ◽  
pp. 1059-1068 ◽  
Author(s):  
Min Ge ◽  
Shanfeng Ma ◽  
Liang Tao ◽  
Sudong Guan
Keyword(s):  
Cardiac Function ◽  
Diabetic Cardiomyopathy ◽  
Diastolic Pressure ◽  
Pure Water ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Control Group ◽  
Sprague Dawley ◽  
Gene Expressions ◽  
Ventricular Systolic Pressure

The relationship between changes of cardiac function and the gene expressions of two major myocardial skeleton proteins, titin and nebulin, and the effect of gypenosides on these gene expressions in diabetic cardiomyopathy rat were explored in the present study. Forty Sprague-Dawley rats were randomly divided into three groups: control group, diabetic cardiomyopathy group and gypenosides-treated diabetic cardiomyopathy group. The diabetic cardiomyopathy was induced in rats by injecting streptozotocin (STZ, 55 mg/kg) intraperitoneally. Seven weeks after the rats suffered from diabetes, the rats were treated with gypenosides 100 mg/kg per day orally for six weeks in gypenosides-treated group. In the meanwhile, the pure water was given to diabetic cardiomyopathy and the control groups. Subsequently, the cardiac functions, including left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), ± dP/dtmax and t–dP/dmaxt, as well as the mRNA content and proteins of titin and nebulin in myocardium were determined. The results indicated that (1) the diabetic cardiomyopathy rats had decreased LVSP and ± dP/dtmax, increased LVEDP, and prolonged t–dP/dtmax than normal rats; (2) LVSP and ± dP/dtmax in diabetic cardiomyopathy rats treated with gypenosides were significantly higher and LVEDP and t–dP/dtmax were significantly lower than those without giving gypenosides; (3) the mRNA contents and proteins of titin and nebulin in diabetic cardiomyopathy rats were remarkably lower than those in the control rats and gypenosides had no effect on mRNA and protein expression levels of titin and nebulin in diabetic cardiomyopathy rats. We conclude that (1) the cardiac function as well as the mRNA expressions of titin and nebulin decreased in diabetic cardiomyopathy rats; (2) gypenosides secure cardiac muscles and their function from diabetic impairment and these beneficial effects of gypenosides are not by changing the expressions of titin and nebulin.

Effect of human urotensin-II infusion on hemodynamics and cardiac function

2003 ◽  
Vol 81 (2) ◽  
pp. 125-128 ◽  
Author(s):  
Ghada S Hassan ◽  
Fazila Chouiali ◽  
Takayuki Saito ◽  
Fu Hu ◽  
Stephen A Douglas ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Diastolic Pressure ◽  
Cardiac Contractility ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Urotensin Ii ◽  
Ventricular Systolic Pressure ◽  
Wide Range ◽  
Dose Dependent Decrease

Recent studies have shown that the vasoactive peptide urotensin-II (U-II) exerts a wide range of action on the cardiovascular system of various species. In the present study, we determined the in vivo effects of U-II on basal hemodynamics and cardiac function in the anesthetized intact rat. Intravenous bolus injection of human U-II resulted in a dose-dependent decrease in mean arterial pressure and left ventricular systolic pressure. Cardiac contractility represented by ±dP/dt was decreased after injection of U-II. However, there was no significant change in heart rate or diastolic pressure. The present study suggests that upregulation of myocardial U-II may contribute to impaired myocardial function in disease conditions such as congestive heart failure.Key words: urotensin-II, rat, infusion, heart.

Abstract 300: Alda-1 Attenuates Acute Ischemia-reperfusion Mediated Cardiac Damage in Aldehyde Dehydrogenase 2 Mutant Diabetic Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Guodong Pan
Keyword(s):  
Aldehyde Dehydrogenase ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Protective Effects ◽  
Diabetic Mice ◽  
Aldehyde Dehydrogenase 2 ◽  
Cardiac Damage ◽  
Western Blots

Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme in heart, can remove 4-hydroxy-2-nonenal (4-HNE), a toxic by-products of oxidative stress induced by diabetes and ischemia-reperfusion (I/R) injury. A common inactivating mutation of ALDH2 (termed ALDH2*2) was found in 8% of the world’s population, which causes lower ALDH2 activity in mutation carriers. We hypothesized that Alda-1, the only known activator of both ALDH2 and ALDH2*2 mutation, is able to protect heart from I/R injury in diabetic mice with/without ALDH2*2 mutation. Adult male ALDH2*2 mutant and C57B6 wild-type (WT) mice at 3-4 months of age were made hyperglycemic with streptozotocin injection (150 mg/kg. i.p.). Three weeks after injection, Alzet osmotic pumps were implanted subcutaneously to deliver Alda-1 (10 mg/kg) or vehicle. Mice were sacrificed after one day of pump implantation. Hearts were isolated and subjected to 30-minute ischemic followed by 90-minute reperfusion in a Langendorff apparatus. The basal myocardial ALDH2 activity in diabetic ALDH2*2 mutant was significantly lower than in diabetic WT mice (0.50±0.23 vs 0.83±0.08 mmol/min/μg, -39.8%, p<0.05). Alda-1 significantly increased myocardial ALDH2 activity in both ALDH2*2 (1.17±0.38 mmol/min/μg, +134.0%, p<0.05) and WT (1.46±0.40 mmol/min/μg, +75.9%, p<0.05) diabetic mice. Compared with vehicle, Alda-1 significantly improved left ventricular pressure (LVP), and decreased infarcted areas (IA) both in ALDH2*2 (LVP: 4.30±2.03 vs 15.77±8.99 mmHg, +266.7%, p<0.05; IA: 75.17%±9.49 vs 40.46%±7.20, -46.2%, p<0.05) and WT (LVP: 14.22±7.92 vs 21.96±4.32 mmHg, +54.4%, p<0.05; IA: 42.44%±8.60 vs 28.61%±8.55, -32.6%, p<0.05) subjected to I/R injury. Western-blots showed that Alda-1 decreased levels of 4-HNE protein adducts, and increased levels of mitochondrial complex V in both ALDH2*2 and WT mice. Our data suggest that one-day Alda-1 treatment can confer cardio-protective effects against I/R injury in ALDH2*2 diabetic mice possibly accelerating the detoxification of toxic 4-HNE and thereby protecting mitochondria.

Chronic alcohol-induced changes in cardiac contractility are not due to changes in the cytosolic Ca2+ transient

1998 ◽  
Vol 275 (1) ◽  
pp. H122-H130 ◽  
Author(s):  
Vincent M. Figueredo ◽  
Kevin C. Chang ◽  
Anthony J. Baker ◽  
S. Albert Camacho
Keyword(s):  
Cardiac Contractility ◽  
Left Ventricular Pressure ◽  
Alcohol Exposure ◽  
Left Ventricular ◽  
Polyacrylamide Gel ◽  
Chronic Alcohol ◽  
Protein Levels ◽  
Chronic Alcohol Exposure ◽  
Induced Changes ◽  
And Control

Long-standing heavy alcohol consumption acts as a chronic stress on the heart. It is thought that alcohol-induced changes of contractility are due to altered Ca2+ handling, but no measurements of cytosolic Ca2+([Ca2+]c) after chronic alcohol exposure have been made. Therefore experiments were performed to determine whether alcohol-induced changes in contractility are due to altered Ca2+ handling by measuring [Ca2+]c(indo 1) in hearts from rats drinking 36% ethanol for 7 mo and age-matched controls. Peak left ventricular pressure was depressed (−16%), whereas rates of contraction (12%) and relaxation (14–20%) were faster in alcohol-exposed hearts. Systolic [Ca2+]c(808 ± 45 vs. 813 ± 45 nM), diastolic [Ca2+]c(195 ± 11 vs. 193 ± 10 nM), and rates of [Ca2+]crise and decline were the same in alcohol-exposed and control hearts. Protein levels of Ca2+-handling proteins, sarcoplasmic reticulum Ca2+-ATPase and phospholamban, were the same in myocytes isolated from alcohol-exposed and control hearts (SDS-polyacrylamide gel). These data suggest that chronic alcohol-induced contractile changes are not due to altered Ca2+ handling but may be due to changes at the level of the myofilament. As a first step in elucidating the mechanism(s) of alcohol-induced changes at the myofilament, we assessed myosin heavy chain (MHC) isoform content (SDS-polyacrylamide gel). α-MHC was decreased relative to β-MHC ( a/ a+ b = 0.55 ± 0.03 vs. 0.66 ± 0.02; P < 0.02) in alcohol-exposed hearts, which cannot account for the observed alcohol-induced contractile changes. In conclusion, changes of myocardial contractility due to chronic alcohol exposure do not result from altered Ca2+ handling but from changes at the level of the myofilament that do not involve MHC isoform shifts.

One-day cold perfusion of bimakalim and butanedione monoxime restores ex situ cardiac function

1996 ◽  
Vol 271 (5) ◽  
pp. H1884-H1892 ◽  
Author(s):  
D. F. Stowe ◽  
B. M. Graf ◽  
S. Fujita ◽  
G. J. Gross
Keyword(s):  
Cardiac Function ◽  
Myocardial Function ◽  
Left Ventricular Pressure ◽  
Katp Channels ◽  
Left Ventricular ◽  
Ex Situ ◽  
Control Group ◽  
Cardiac Efficiency ◽  
Time Control ◽  
Butanedione Monoxime

Bimakalim (Bim), an opener of ATP-sensitive K+ (KATP) channels, was given alone or with 2,3-butanedione monoxime (BDM), a reversible uncoupler of contractility, to protect myocardial function during 1 day of hypothermia. Left ventricular pressure (LVP), coronary flow (CF), percent O2 extraction (%O2E), and cardiac efficiency were measured in 96 isolated, perfused guinea pig hearts divided into seven groups: 1) cold control (no drugs); 2) BDM; 3) Bim; 4) BDM + Bim; 5) BDM + glibenclamide (Glib, a blocker of KATP channels); 6) BDM + Bim + Glib; and 7) time control (6 h warm perfusion only). Drugs were given before, during, and initially after 22 h of low CF at 3.8 degrees C. At 26 h (cold groups) or 4 h (warm group) LVP (mmHg; means +/- SE) was similar for time control (94 +/- 4) and BDM + Bim (92 +/- 4) groups, lower and equivalent in the BDM (65 +/- 7) and BDM + Bim + Glib (64 +/- 7) groups, but LVP was higher than in the Bim group (46 +/- 3), and lowest in the cold control (30 +/- 8) group. In addition, only in the BDM + Bim group were basal CF, %O2E, and cardiac efficiency returned to values obtained in the time control group. Epinephrine increased LVP to that of the time control (106 +/- 3) group only in the BDM + Bim group (106 +/- 3) after hypothermia, and CF increases with adenosine, 5-hydroxytryptamine, and nitroprusside were similar to that of the time control group only in the BDM + Bim group after hypothermia. All of the effects of Bim were reversed by Glib. These results indicate that Bim, given with BDM, effectively preserves myocardial function and metabolism as well as inotropic and vasodilatory reserve during long-term hypothermic preservation as if the 1-day hypothermic state had not been instituted. Because the beneficial effects of Bim are blocked by Glib, the protective effect of Bim likely results from maintained KATP channel opening. Treatment with exogenous KATP openers may prove useful in preserving cardiac function in the transplanted heart.

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