Effects of chronic activation of peroxisome proliferator-activated receptor-alpha or high-fat feeding in a rat infarct model of heart failure

Intracardiac accumulation of lipid and related intermediates (e.g., ceramide) is associated with cardiac dysfunction and may contribute to the progression of heart failure (HF). Overexpression of nuclear receptor peroxisome proliferator-activated receptor-alpha (PPARalpha) increases intramyocellular ceramide and left ventricular (LV) dysfunction. We tested the hypothesis that activation of fatty acid metabolism with fat feeding or a PPARalpha agonist increases myocardial triglyceride and/or ceramide and exacerbates LV dysfunction in HF. Rats with infarct-induced HF (n = 38) or sham-operated rats (n = 10) were either untreated (INF, n = 10), fed a high-fat diet (45% kcal fat, INF + Fat, n = 15), or fed the PPARalpha agonist fenofibrate (150 mg.kg(-1).day(-1), INF + Feno, n = 13) for 12 wk. LV ejection fraction was significantly reduced with HF (49 +/- 6%) compared with sham operated (86 +/- 2%) with no significant differences in ejection fraction (or other functional or hemodynamic measures) among the three infarcted groups. Treatment with the PPARalpha agonist resulted in LV hypertrophy (24% increase in LV/body mass ratio) and induced mRNAs encoding for PPARalpha-regulated genes, as well as protein expression and activity of medium chain acyl-CoA dehydrogenase (compared with INF and INF + Fat groups). Myocardial ceramide content was elevated in the INF group compared with sham-operated rats, with no further change in the INF + Fat or INF + Feno groups. Myocardial triglyceride was unaffected by infarction but increased in the INF + Fat group. In conclusion, LV dysfunction and dilation are not worsened despite upregulation of the fatty acid metabolic pathway and LV hypertrophy or accumulation of myocardial triglyceride in the rat infarct model of HF.     

Heart failure progression is accelerated following myocardial infarction in type 2 diabetic rats

Clinical studies have shown a greater incidence of myocardial infarction in diabetic patients, and following an infarction, diabetes is associated with an increased risk for the development of left ventricular (LV) dysfunction and heart failure. The goal of this study was to determine if the progression of heart failure following myocardial infarction in type 2 diabetic (T2D) rats is accelerated compared with nondiabetic rats. Male nondiabetic Wistar-Kyoto (WKY) and T2D Goto-Kakizaki (GK) rats underwent coronary artery ligation or sham surgery to induce heart failure. Postligation (8 and 20 wk), two-dimensional echocardiography and LV pressure measurements were made. Heart failure progression, as assessed by enhanced LV remodeling and contractile dysfunction, was accelerated 8 wk postligation in the T2D animals. LV remodeling was evident from increased end-diastolic and end-systolic diameters and areas in the GK compared with the WKY infarcted group. Furthermore, enhanced LV contractile dysfunction was evident from a greater deterioration in fractional shortening and enhanced myocardial performance index (an index of global LV dysfunction) in the GK infarcted group. This accelerated progression was accompanied by greater increases in atrial natriuretic factor and skeletal alpha-actin (gene markers of heart failure and hypertrophy) mRNA levels in GK infarcted hearts. Despite similar decreases in metabolic gene expression (i.e., peroxisome proliferator-activated receptor-alpha-regulated genes associated with fatty acid oxidation) between infarcted WKY and GK rat hearts, myocardial triglyceride levels were elevated in the GK hearts only. These results, demonstrating enhanced remodeling and LV dysfunction 8 wk postligation provide evidence of an accelerated progression of heart failure in T2D rats.     

New aspects of impaired mitochondrial function in heart failure

This minireview focuses on the impairment of function in cardiac mitochondria in heart failure (HF). It is generally accepted that chronic energy starvation leads to cardiac mechanical dysfunction in HF. Mitochondria are the primary ATP generator for the heart. Current evidence suggests that the assembly of the electron transport chain (ETC) into respirasomes provides structural support for mitochondrial oxidative phosphorylation by facilitating electron channeling and perhaps by preventing electron leak and superoxide production. Defects have been purported to occur in the individual ETC complexes or components of the phosphorylation apparatus in HF, but these defects have not been linked to impaired mitochondrial function. Moreover, studies that reported decreased mitochondrial oxidative phosphorylation in HF did not identify the site of the defect. We propose a sequential mechanistic pathway in which the decrease in functional respirasomes in HF is the primary event causing decreased oxidative phosphorylation and increased reactive oxygen species production, leading to a progressive decrease in cardiac performance.     

Vitamins C and E attenuate apoptosis, beta-adrenergic receptor desensitization, and sarcoplasmic reticular Ca2+ ATPase downregulation after myocardial infarction

Oxidative stress plays an important role in mediating ventricular remodeling and dysfunction in heart failure (HF), but its mechanism of action has not been fully elucidated. In this study we determined whether a combination of antioxidant vitamins reduced myocyte apoptosis, beta-adrenergic receptor desensitization, and sarcoplasmic reticular (SR) Ca2+ ATPase downregulation in HF after myocardial infarction (MI) and whether these effects were associated with amelioration of left ventricular (LV) remodeling and dysfunction. Vitamins (vitamin C 300 mg and vitamin E 300 mg) were administered to rabbits 1 week after MI or sham operation for 11 weeks. The results showed that MI rabbits exhibited cardiac dilation and LV dysfunction measured by fractional shortening and the maximal rate of pressure rise (dP/dt), an index of contractility. These changes were associated with elevation of oxidative stress, decreases of mitochondrial Bcl-2 and cytochrome c proteins, increases of cytosolic Bax and cytochrome c proteins, caspase 9 and caspase 3 activities and myocyte apoptosis, and downregulation of beta-adrenergic receptor sensitivity and SR Ca2+ ATPase. Combined treatment with vitamins C and E diminished oxidative stress, increased mitochondrial Bcl-2 protein, decreased cytosolic Bax, prevented cytochrome c release from mitochondria to cytosol, reduced caspase 9 and caspase 3 activities and myocyte apoptosis, blocked beta-adrenergic receptor desensitization and SR Ca2+ ATPase downregulation, and attenuated LV dilation and dysfunction in HF after MI. The results suggest that antioxidant therapy may be beneficial in HF.     

Differential effects of saturated and unsaturated fatty acid diets on cardiomyocyte apoptosis, adipose distribution, and serum leptin

Fatty acids are the primary fuel for the heart and are ligands for peroxisome proliferator-activated receptors (PPARs), which regulate the expression of genes encoding proteins involved in fatty acid metabolism. Saturated fatty acids, particularly palmitate, can be converted to the proapoptotic lipid intermediate ceramide. This study assessed cardiac function, expression of PPAR-regulated genes, and cardiomyocyte apoptosis in rats after 8 wk on either a low-fat diet [normal chow control (NC); 10% fat calories] or high-fat diets composed mainly of either saturated (Sat) or unsaturated fatty acids (Unsat) (60% fat calories) (n = 10/group). The Sat group had lower plasma insulin and leptin concentrations compared with the NC or Unsat groups. Cardiac function and mass and body mass were not different. Cardiac triglyceride content was increased in the Sat and Unsat groups compared with NC (P < 0.05); however, ceramide content was higher in the Sat group compared with the Unsat group (2.9 +/- 0.2 vs. 1.4 +/- 0.2 nmol/g; P < 0.05), whereas the NC group was intermediate (2.3 +/- 0.3 nmol/g). The number of apoptotic myocytes, assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, was higher in the Sat group compared with the Unsat group (0.28 +/- 0.05 vs. 0.17 +/- 0.04 apoptotic cells/1,000 nuclei; P < 0.04) and was positively correlated to ceramide content (P < 0.02). Both high-fat diets increased the myocardial mRNA expression of the PPAR-regulated genes encoding uncoupling protein-3 and pyruvate dehydrogenase kinase-4, but only the Sat diet upregulated medium-chain acyl-CoA dehydrogenase. In conclusion, dietary fatty acid composition affects cardiac ceramide accumulation, cardiomyocyte apoptosis, and expression of PPAR-regulated genes independent of cardiac mass or function.     

Deleterious effects of sugar and protective effects of starch on cardiac remodeling, contractile dysfunction, and mortality in response to pressure overload

Little is known about the effects of the composition of dietary carbohydrate on the development of left ventricular (LV) hypertrophy (LVH) and heart failure (HF) under conditions of pressure overload. The objective of this study was to determine the effect of carbohydrate composition on LVH, LV function, and mortality in a mouse model of chronic pressure overload. Male C57BL/6J mice of 6 wk of age (n = 14-16 mice/group) underwent transverse aortic constriction (TAC) or sham surgery and were fed either standard chow (STD; 32% corn starch, 35% sucrose, 3% maltodextrin, and 10% fat expressed as a percent of the total energy), high-starch chow (58% corn starch, 12% maltodextrin, and 10% fat), or high-fructose chow (9% corn starch, 61% fructose, and 10% fat). After 16 wk of treatment, mice with TAC fed the STD or high-fructose diets exhibited increased LV mass, larger end-diastolic and end-systolic diameters, and decreased ejection fraction compared with sham. The high-starch diet, in contrast, prevented changes in LV dimensions and contractile function. Cardiac mRNA for myosin heavy chain-beta was increased dramatically in the fructose-fed banded animals, as was mortality (54% compared with 8% and 29% in the starch and STD banded groups, respectively). In conclusion, a diet high in simple sugar was deleterious, resulting in the highest mortality and expression of molecular markers of cardiac dysfunction in TAC animals compared with sham, whereas a high-starch diet blunted mortality, increases in cardiac mass, and contractile dysfunction.     

Cellular mechanisms of burn-related changes in contractility and its prevention by mesenteric lymph ligation

Major burn injury results in impairment of left ventricular (LV) contractile function. There is strong evidence to support the involvement of gut-derived factor(s) transported in mesenteric lymph in the development of burn-related contractile dysfunction; i.e., mesenteric lymph duct ligation (LDL) prevents burn-related contractile depression. However, the cellular mechanisms for altered myocardial contractility of postburn hearts are largely unknown, and the cellular basis for the salutary effects of LDL on cardiac function have not been investigated. We examined contractility, Ca(2+) transients, and L-type Ca(2+) currents (I(Ca)) in LV myocytes isolated from four groups of rats: 1) sham burn, 2) sham burn with LDL (sham + LDL), 3) burn ( approximately 40% of total body surface area burn), and 4) burn with LDL (burn + LDL). Myocytes isolated from hearts at 24 h postburn had a depressed contractility ( approximately 20%) at baseline and blunted responsiveness to elevation of bath Ca(2+). Myocyte contractility was comparable in sham + LDL and sham burn hearts. LDL completely prevented burn-related changes in myocyte contractility. Mechanistically, the decrease in contractility in myocytes from postburn hearts occurred with a decrease in the amplitude of Ca(2+) transients ( approximately 20%) without changes in resting Ca(2+) or Ca(2+) content of the sarcoplasmic reticulum. On the other hand, I(Ca) density was decreased ( approximately 30%) in myocytes from postburn hearts, with unaltered voltage-dependent properties. Thus burn-related myocardial contractile dysfunction is linked with depressed myocyte contractility associated with a decrease in I(Ca) density. These findings also provide strong evidence that mesenteric lymph is involved in the onset of burn-related cardiomyocyte dysfunction.     

Temporal pattern of left ventricular structural and functional remodeling following reversal of volume overload heart failure

Current surgical management of volume overload-induced heart failure (HF) leads to variable recovery of left ventricular (LV) function despite a return of LV geometry. The mechanisms that prevent restoration of function are unknown but may be related to the timing of intervention and the degree of LV contractile impairment. This study determined whether reduction of aortocaval fistula (ACF)-induced LV volume overload during the compensatory stage of HF results in beneficial LV structural remodeling and restoration of pump function. Rats were subjected to ACF for 4 wk; a subset then received a load-reversal procedure by closing the shunt using a custom-made stent graft approach. Echocardiography or in vivo pressure-volume analysis was used to assess LV morphology and function in sham rats; rats subjected to 4-, 8-, or 15-wk ACF; and rats subjected to 4-wk ACF followed by 4- or 11-wk reversal. Structural and functional changes were correlated to LV collagen content, extracellular matrix (ECM) proteins, and hypertrophic markers. ACF-induced volume overload led to progressive LV chamber dilation and contractile dysfunction. Rats subjected to short-term reversal (4-wk ACF + 4-wk reversal) exhibited improved chamber dimensions (LV diastolic dimension) and LV compliance that were associated with ECM remodeling and normalization of atrial and brain natriuretic peptides. Load-independent parameters indicated LV systolic (preload recruitable stroke work, Ees) and diastolic dysfunction (tau, arterial elastance). These changes were associated with an altered α/β-myosin heavy chain ratio. However, these changes were normalized to sham levels in long-term reversal rats (4-wk ACF + 11-wk reversal). Acute hemodynamic changes following ACF reversal improve LV geometry, but LV dysfunction persists. Gradual restoration of function was related to normalization of eccentric hypertrophy, LV wall stress, and ECM remodeling. These results suggest that mild to moderate LV systolic dysfunction may be an important indicator of the ability of the myocardium to remodel following the reversal of hemodynamic overload.     

Progressive left ventricular remodeling, myocyte apoptosis, and protein signaling cascades after myocardial infarction in rabbits

To determine the temporal changes in oxidative stress, mitogen-activated protein (MAP) kinases and mitochondrial apoptotic proteins, and their relationship to myocyte apoptosis in the remote noninfarcted myocardium after myocardial infarction (MI), rabbits were randomly assigned to either coronary artery ligation to produce MI or sham operation. The animals were sacrificed at 1, 4, 8, or 12 weeks after coronary artery occlusion. Sham rabbits were sacrificed at 12 weeks after surgery. MI rabbits exhibited progressive increases of left ventricular (LV) end-diastolic pressure and end-diastolic dimension, and progressive decreases of LV fractional shortening and dP/dt over 12 weeks. The LV remodeling with LV chamber dilation and LV systolic dysfunction was temporally associated with progressive increases of cardiac oxidative stress as evidenced by decreased myocardial reduced-to-oxidized-glutathione ratio and increased myocardial 8-hydroxydeoxyguanosine and myocyte apoptosis. The ERK and JNK activities were decreased while p38 MAP kinase activity was increased with age of MI. The extent of p38 MAP kinase activation correlated with Bcl-2 phosphorylation. Bcl-2 protein was decreased in both mitochondrial and cytosolic fractions with age of MI. Bax protein was increased in both mitochondrial and cytosolic fractions. Cytochrome c was reduced in mitochondrial fraction and increased in cytosolic fraction in a time-dependent manner after MI. Cleaved caspase 9 and caspase 3 proteins were time-dependently increased after MI. These data suggest that p38 MAP kinase activation is not only time-dependent after MI, but also correlates with oxidative stress, Bcl-2 phosphorylation, and myocyte apoptosis. These changes in the remote noninfarcted myocardium may contribute to LV remodeling and dysfunction after MI.     

Losartan prevents contractile dysfunction in rat myocardium after left ventricular myocardial infarction

We studied the effects of chronic losartan (Los) treatment on contractile function of isolated right ventricular (RV) trabeculae from rat hearts 12 wk after left ventricular (LV) myocardial infarction (MI) had been induced by ligation of the left anterior descending artery at 4 wk of age. After recovery, one-half of the animals were started on Los treatment (MI+Los; 30 mg x kg(-1) x day(-1) per os); the remaining animals were not treated (MI group). Rats without infarction or Los treatment served as controls (Con group). MI resulted in increases in LV and RV weight and unstressed LV cavity diameter; these were partially prevented by Los treatment. The active peak twitch force-sarcomere length relation was depressed in MI compared with either Con or MI+Los. Likewise, maximum Ca2+ saturated twitch force was depressed in MI, whereas twitch relaxation and twitch duration were prolonged. Myofilament function, as measured in skinned trabeculae, was not significantly different among the Con, MI, and MI+Los groups. We conclude that Los prevents contractile dysfunction in rat RV trabeculae after LV MI. Our results suggest that the beneficiary effect of Los treatment results not from improved myofilament function but rather from improved myocyte Ca2+ homeostasis.     

Cardiac mitochondria in heart failure: normal cardiolipin profile and increased threonine phosphorylation of complex IV

Mitochondrial dysfunction is a major contributor in heart failure (HF). We investigated whether the decrease in respirasome organization reported by us previously in cardiac mitochondria in HF is due to changes in the phospholipids of the mitochondrial inner membrane or modifications of the subunits of the electron transport chain (ETC) complexes. The contents of the main phospholipid species, including cardiolipin, as well as the molecular species of cardiolipin were unchanged in cardiac mitochondria in HF. Oxidized cardiolipin molecular species were not observed. In heart mitochondria isolated from HF, complex IV not incorporated into respirasomes exhibits increased threonine phosphorylation. Since HF is associated with increased adrenergic drive to cardiomyocytes, this increased protein phosphorylation might be explained by the involvement of cAMP-activated protein kinase. Does the preservation of cAMP-induced phosphorylation changes of mitochondrial proteins or the addition of exogenous cAMP have similar effects on oxidative phosphorylation? The usage of phosphatase inhibitors revealed a specific decrease in complex I-supported respiration with glutamate. In saponin-permeabilized cardiac fibers, pre-incubation with cAMP decreases oxidative phosphorylation due to a defect localized at complex IV of the ETC inter alia. We propose that phosphorylation of specific complex IV subunits decreases oxidative phosphorylation either by limiting the incorporation of complex IV in supercomplexes or by decreasing supercomplex stability.     

Echocardiographic detection of congestive heart failure in postinfarction rats

In studies of congestive heart failure (CHF) treatment, it is essential to select animals with a similar degree of cardiac dysfunction. However, this is difficult to establish without hemodynamic evaluation in rat postinfarction-induced CHF. This study aimed to diagnose CHF in long-term follow-up postinfarction rats using only echocardiographic criteria through a J-tree cluster analysis and Fisher's linear discriminant function. Two sets of sham and infarcted rats were studied. The first was used to perform cluster analysis and the second to prospectively validate the results. Six months after inducing myocardial infarction (MI), rats were subjected to transthoracic echocardiography. Infarct size was measured by histological analysis. Six echocardiographic variables were used in the cluster analysis: left ventricular (LV) systolic dimension, LV diastolic dimension-to-body weight ratio, left atrial diameter-to-body weight ratio, LV posterior wall shortening velocity, E wave, and isovolumetric relaxation time. Cluster analysis joined the rats into one sham and two MI groups. One MI cluster had more severe anatomical and echocardiographic changes and was called MI with heart failure (MI/HF+, n = 24, infarct size: 42.7 ± 5.8%). The other had less severe changes and was called MI without heart failure (MI/HF-, n = 11, infarct size: 32.3 ± 9.9%; P < 0.001 vs. MI/HF+). Three rats with small infarct size (21.6 ± 2.2%) presenting mild cardiac alterations were misallocated in the sham group. Fisher's linear discriminant function was built using these groups and used to prospectively classify additional groups of sham-operated (n = 20) and infarcted rats (n = 57) using the same echocardiographic parameters. The discriminant function therefore detected CHF with 100% specificity and 80% sensitivity considering allocation in MI/HF+ and sham group, and 100% specificity and 58.8% sensitivity considering MI/HF+ and MI/HF- groups, taking into account pathological criteria of CHF diagnosis. Echocardiographic analysis can be used to accurately predict congestive heart failure in postinfarction rats.     

Globular adiponectin resistance develops independently of impaired insulin-stimulated glucose transport in soleus muscle from high-fat-fed rats

High-fat (HF) diets induce insulin resistance and alter lipid metabolism, although controversy exists regarding the impact of saturated vs. polyunsaturated fats. Adiponectin (Ad) stimulates fatty acid (FA) oxidation and improves insulin sensitivity in humans and rodents, due in part to the activation of AMP-activated protein kinase (AMPK) and subsequent deactivation of acetyl coenzyme A carboxylase (ACC). In genetically obese, diabetic mice, this acute stimulatory effect on AMPK in muscle is lost. The ability of a HF diet to induce skeletal muscle Ad resistance has not been examined. The purpose of this study was to determine whether Ad's effects on FA oxidation and AMPK/ACC would be reduced following different HF diets, and if this coincided with the development of impaired maximal insulin-stimulated glucose transport. Rats were fed a control (10% kcal fat, CON), high unsaturated fat (60% kcal safflower oil, SAFF), or high saturated fat diet (60% kcal lard, LARD) for 4 wk. Following the dietary intervention, glucose transport, lipid metabolism, and AMPK/ACC phosphorylation were measured in the presence and absence of globular Ad (gAd, 2.5 microg/ml) in isolated soleus muscle. LARD rats showed reduced rates of maximal insulin-stimulated glucose transport compared with CON and SAFF (+68 vs. +172 and +184%, P < or = 0.001). gAd increased pACC (+25%, P < or = 0.01) and FA oxidation (+28%, P < or = 0.05) in CON rats, but not in either HF group. Thus 4 wk of HF feeding results in the loss of gAd stimulatory effect on ACC phosphorylation and muscle FA oxidation, and this can occur independently of impaired maximal insulin-stimulated glucose transport.     

Attenuation of heart failure due to coronary stenosis by ACE inhibitor and angiotensin receptor blocker

It is not known how the angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) attenuate heart failure (HF) in viable ischemic hearts. To assess HF in a rat coronary stenosis (CS) model, we administered vehicle and quinapril or candesartan (or both) orally for 12 wk. Compared with the sham group, the vehicle group showed impaired myocardial perfusion, impaired coronary endothelial nitric oxide (NO) function in vitro, exhausted myocardial mitochondrial respiration, larger left ventricular (LV) dimensions and lower ejection fraction, lower LV rate of pressure development over time (dP/dt), lower slopes of LV end-systolic pressure-dimension relations (ESPDRs), and increased myocardial fibrosis. Treatment with quinapril or candesartan ameliorated these parameters without modifying the epicardial CS severity. Moreover, their combination maintained similar myocardial perfusion, despite a trend toward lower blood pressure, and showed distinctive neurohumoral modulation, normalized mitochondrial respiration, and increased ESPDR slopes. Thus improved myocardial blood flow and coronary flow reserve by quinapril or candesartan are the key to alleviate CS-induced HF, and their combination may have a therapeutic significance partly through ameliorated mitochondrial respiration and improved LV systolic function.     

Progressive left ventricular remodeling and apoptosis late after myocardial infarction in mouse heart

We tested the hypothesis that left ventricular (LV) remodeling late after myocardial infarction (MI) is associated with myocyte apoptosis in myocardium remote from the infarcted area and is related temporally to LV dilation and contractile dysfunction. One, four, and six months after MI caused by coronary artery ligation, LV volume and contractile function were determined using an isovolumic balloon-in-LV Langendorff technique. Apoptosis and nuclear morphology were determined by terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) and Hoechst 33258 staining. Progressive LV dilation 1-6 mo post-MI was associated with reduced peak LV developed pressure (LVDP). In myocardium remote from the infarct, there was increased wall thickness and expression of atrial natriuretic peptide mRNA consistent with reactive hypertrophy. There was a progressive increase in the number of TUNEL-positive myocytes from 1 to 6 mo post-MI (2.9-fold increase at 6 mo; P < 0. 001 vs. sham). Thus LV remodeling late post-MI is associated with increased apoptosis in myocardium remote from the area of ischemic injury. The frequency of apoptosis is related to the severity of LV dysfunction.     

Double knockout of Akt2 and AMPK accentuates high fat diet-induced cardiac anomalies through a cGAS-STING-mediated mechanism

High fat diet intake contributes to undesired cardiac geometric and functional changes although the underlying mechanism remains elusive. Akt and AMPK govern to cardiac homeostasis. This study examined the impact of deletion of Akt2 (main cardiac isoform of Akt) and AMPKα2 on high fat diet intake-induced cardiac remodeling and contractile anomalies and mechanisms involved. Cardiac geometry, contractile, and intracellular Ca²⁺ properties were evaluated using echocardiography, IonOptix® edge-detection and fura-2 techniques in wild-type (WT) and Akt2-AMPK double knockout (DKO) mice receiving low fat (LF) or high fat (HF) diet for 4 months. Our results revealed that fat diet intake elicit obesity, cardiac remodeling (hypertrophy, LV mass, LVESD, and cross-sectional area), contractile dysfunction (fractional shortening, peak shortening, maximal velocity of shortening/relengthening, time-to-90% relengthening, and intracellular Ca²⁺ handling), ultrastructural disarray, apoptosis, O₂⁻, inflammation, dampened autophagy and mitophagy. Although DKO did not affect these parameters, it accentuated high fat diet-induced cardiac remodeling and contractile anomalies. High fat intake upregulated levels of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and STING phosphorylation while suppressing phosphorylation of ULK1 (Ser⁷⁵⁷ and Ser⁷⁷⁷), with a more pronounced effect in DKO mice. In vitro data revealed that inhibition of cGAS and STING using PF-06928215 and Astin C negated palmitic acid-induced cardiomyocyte contractile dysfunction. Biological function analysis for all differentially expressed genes (DEGs) depicted that gene ontology terms associated with Akt and AMPK signaling processes were notably changed in high fat-fed hearts. Our data indicate that Akt2-AMPK ablation accentuated high fat diet-induced cardiac anomalies possibly through a cGAS-STING-mechanism.     

Cyclosporin A inhibits cardiac hypertrophy and enhances cardiac dysfunction during postinfarction failure in rats

Calcineurin has recently been implicated as a mediator in the signaling pathways that transform intracellular calcium signals to the phenotype of myocardial hypertrophy. The present study was conducted to examine the effects of cyclosporin A (CsA), an inhibitor of calcineurin, on myocardial hypertrophy and remodeling during congestive heart failure (CHF) in rats. After ligation of the left coronary artery, rats were randomized to treatment with CsA or vehicle for 14 days. Compared with vehicle, CsA substantially attenuated myocardial hypertrophy in the CHF rats as assessed by alterations in ventricular weight-to-tibial length ratios (P < 0.05). Myocardial gene expression of skeletal alpha-actin was also reduced in the failing left ventricle (LV) after treatment with CsA (P < 0. 05), although the mRNA levels were still substantially elevated relative to those of sham rats. CsA-induced inhibition of compensatory myocardial hypertrophy in the CHF rats led to increased dilatation of the LV cavity and reduced fractional shortening and peak positive and negative first derivatives of LV pressure (P < 0. 05). Plasma renin and endothelin-1 levels were increased in the CHF-CsA rats, providing humoral cues of aggravated cardiac function. Thus this study supports a crucial role of calcineurin-dependent pathways in the mechanisms of compensatory myocardial hypertrophy during CHF. In addition, our data indicate that inhibition of compensatory myocardial hypertrophy exerts detrimental effects on cardiac remodeling and function after myocardial infarction.     

Remodeling of the chronic severely failing ischemic sheep heart after coronary microembolization: functional, energetic, structural, and cellular responses

The mandatory use of pharmacotherapy in human heart failure (HF) impedes further study of natural history and remodeling mechanisms. We created a sheep model of chronic, severe, ischemic HF [left ventricular (LV) ejection fraction (LVEF) <35% stable over 4 wk] by selective coronary microembolization under general anesthesia and followed hemodynamic, energetic, neurohumoral, structural, and cellular responses over 6 mo. Thirty-eight sheep were induced into HF (58% success), with 23 sheep followed for 6 mo (21 sheep with sufficient data for analysis) after the LVEF stabilized (median of 3 embolizations). Early doubling of LV end-diastolic pressure persisted, as did increases in LV end-diastolic volume, LV wall stress, and LV wall thinning. Contractile impairment (LV end-systolic elastance, LV preload recruitable stroke work, and dobutamine-responsive contractile reserve) and diastolic dysfunction also remained stable. Cardiac mechanical energy efficiency did not recover. Plasma atrial natriuretic peptide levels remained elevated, but rises in plasma aldosterone and renin activity were transient. Collagen content increased 170%, the type I-to-III phenotype ratio doubled in the LV, but right ventricular collagen remained unaltered. Fas ligand cytokine levels correlated with expression of both caspase-3 and -2, suggesting a link in the apoptotic "death cascade." Caspase-3 activity also bore a close relationship to LV meridional wall stress calculated from echocardiographic and intraventricular pressure measurements. We concluded that the stability of chronic untreated severe ischemic HF depends on the recruitment of myocardial remodeling mechanisms that involve an interaction among hemodynamic load, contractile efficiency/energetics, neurohumoral activation, response of the extracellular matrix, wall stress, and the myocyte apoptotic pathway.     

The antioxidant tempol attenuates pressure overload-induced cardiac hypertrophy and contractile dysfunction in mice fed a high-fructose diet

We have previously shown that high-sugar diets increase mortality and left ventricular (LV) dysfunction during pressure overload. The mechanisms behind these diet-induced alterations are unclear but may involve increased oxidative stress in the myocardium. The present study examined whether high-fructose feeding increased myocardial oxidative damage and exacerbated systolic dysfunction after transverse aortic constriction (TAC) and if this effect could be attenuated by treatment with the antioxidant tempol. Immediately after surgery, TAC and sham mice were assigned to a high-starch diet (58% of total energy intake as cornstarch and 10% fat) or high-fructose diet (61% fructose and 10% fat) with or without the addition of tempol [0.1% (wt/wt) in the chow] and maintained on the treatment for 8 wk. In response to TAC, fructose-fed mice had greater cardiac hypertrophy (55.1% increase in the heart weight-to-tibia length ratio) than starch-fed mice (22.3% increase in the heart weight-to-tibia length ratio). Treatment with tempol significantly attenuated cardiac hypertrophy in fructose-fed TAC mice (18.3% increase in the heart weight-to-tibia ratio). Similarly, fructose-fed TAC mice had a decreased LV area of fractional shortening (from 38+/-2% in sham to 22+/-4% in TAC), which was prevented by tempol treatment (33+/-3%). Markers of lipid peroxidation in fructose-fed TAC hearts were also blunted by tempol. In conclusion, tempol significantly blunted markers of cardiac hypertrophy, LV remodeling, contractile dysfunction, and oxidative stress in fructose-fed TAC mice.