RESUMO

Aim: To evaluate the influence of swimming training on calcium responsiveness of the myocardium of rats with different infarction sizes (MI). Method: female Wistar rats, sedentary sham (SS = 14), sedentary moderate MI (SMI = 8) and sedentary large MI (SLI = 10) were compared to trained sham (TS = 16), trained moderate MI (TMI = 9) and trained large MI (TLI = 10). After 4 weeks of MI, the animals swam for 60 min/day, 5 days/week, for additional 8 weeks. Papillary muscles of the left ventricle were subjected to different concentrations of extracellular calcium. Inotropism was evaluated through the developed tension (DT), the maximum positive value of the first temporal derivation (+Td/td) and the time to peak tension (TPT). Lusitropism was evaluated by the maximum negative value of the first temporal derivation (-Td/td) and time to 50% relaxation (50%TR). Statistical significance was determined using multivariate analysis of variance and a Hotelling T2 test for the absolute power values of all four extracellular calcium concentrations (p < 0.05). Results: MI depressed inotropism (from 17% to 51%) and lusitropism (from 22% to 54%) of the sedentary rats, but exercise attenuated the losses, especially regarding + dT/dt, TPT, -dT/dt and 50%TR. Exercise attenuated the decrease in myocardial responsiveness, proportionally to the size of the MI. Conclusion: Myocardial calcium responsiveness is favorably affected in animals with moderate and large MI after swimming exercise.

RESUMO

AIMS: Emerging evidence suggests the existence of a crosstalk between dipeptidyl peptidase 4 (DPP4) and the renin-angiotensin system (RAS). Therefore, combined inhibition of DPP4 and RAS may produce similar pharmacological effects rather than being additive. This study tested the hypothesis that combining an inhibitor of DPP4 with an angiotensin II (Ang II) receptor blocker does not provide additional cardioprotection compared to monotherapy in heart failure (HF) rats. MAIN METHODS: Male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were assigned into four groups and received vehicle (water), vildagliptin, valsartan, or both drugs, for four weeks by oral gavage. KEY FINDINGS: Vildagliptin and valsartan in monotherapy reduced LV hypertrophy, alleviated cardiac interstitial fibrosis, and improved systolic and diastolic function in HF rats, with no additional effect of combination treatment. HF rats displayed higher cardiac and serum DPP4 activity and abundance than sham. Surprisingly, not only vildagliptin but also valsartan in monotherapy downregulated the catalytic function and expression levels of systemic and cardiac DPP4. Moreover, vildagliptin and valsartan alone or in combination comparably upregulate the components of the cardiac ACE2/Ang-(1-7)/MasR while downregulating the ACE/Ang II/AT1R axis. SIGNIFICANCE: Vildagliptin or valsartan alone is as effective as combined to treat cardiac dysfunction and remodeling in experimental HF. DPP4 inhibition downregulates classic RAS components, and pharmacological RAS blockade downregulates DPP4 in the heart and serum of HF rats. This interplay between DPP4 and RAS may affect HF progression and pharmacotherapy.

Assuntos

Dipeptidil Peptidase 4 , Insuficiência Cardíaca , Animais , Dipeptidil Peptidase 4/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Masculino , Ratos , Ratos Wistar , Sistema Renina-Angiotensina , Valsartana/farmacologia , Valsartana/uso terapêutico , Vildagliptina/farmacologia , Vildagliptina/uso terapêutico

RESUMO

INTRODUCTION: Ischemic heart disease is the leading cause of death worldwide, and interventions to reduce myocardial infarction (MI) complications are widely researched. Photobiomodulation therapy (PBMT) has altered multiple biological processes in tissues and organs, including the heart. OBJECTIVES: This study aimed to assess the temporal effects of PBMT on cardiac fibrosis activation after MI in rats. In this proof-of-concept study, we monitored the change in expression patterns over time of genes and microRNAs (miRNAs) involved in the formation of cardiac fibrosis post-MI submitted to PBMT. MATERIALS AND METHODS: Experimental MI was induced, and PBMT was applied shortly after coronary artery ligation (laser light of wavelength 660 nm, 15 mW of power, energy density 22.5 J/cm2 , 60 seconds of application, irradiated area 0.785 cm2 , fluence 1.1 J/cm2 ). Ventricular septal samples were collected at 30 minutes, 3, 6, 24 hours, and 3 days post-MI to determine temporal PBMT's effects on messenger RNA (mRNA) expression associated with cardiac fibrosis activation and miRNAs expression. RESULTS: PBMT, when applied after ischemia, reversed the changes in mRNA expression of myocardial extracellular matrix genes induced by MI. Surprisingly, PBMT modified cardiac miRNAs expression related to fibrosis replacement in the myocardium. Expression correlations between myocardial mRNAs were assessed. The correlation coefficient between miRNAs and target mRNAs was also determined. A positive correlation was detected among miR-21 and transforming growth factor beta-1 mRNA. The miR-29a expression negatively correlated to Col1a1, Col3a1, and MMP-2 mRNA expressions. In addition, we observed that miR-133 and Col1a1 mRNA were negatively correlated. CONCLUSION: The results suggest that PBMT, through the modulation of gene transcription and miRNA expressions, can interfere in cardiac fibrosis activation after MI, mainly reversing the signaling pathway of profibrotic genes.

Assuntos

Terapia com Luz de Baixa Intensidade , MicroRNAs , Infarto do Miocárdio , Animais , Fibrose , MicroRNAs/genética , MicroRNAs/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/radioterapia , RNA Mensageiro/genética , Ratos

RESUMO

The relationship between disturbances in glucose homeostasis and heart failure (HF) progression is bidirectional. However, the mechanisms by which HF intrinsically impairs glucose homeostasis remain unknown. The present study tested the hypothesis that the bioavailability of intact glucagon-like peptide-1 (GLP-1) is affected in HF, possibly contributing to disturbed glucose homeostasis. Serum concentrations of total and intact GLP-1 and insulin were measured after an overnight fast and 15 min after the ingestion of a mixed breakfast meal in 49 non-diabetic patients with severe HF and 40 healthy control subjects. Similarly, fasting and postprandial serum concentrations of these hormones were determined in sham-operated rats, and rats with HF treated with an inhibitor of the GLP-1-degrading enzyme dipeptidyl peptidase-4 (DPP4), vildagliptin, or vehicle for 4 weeks. We found that HF patients displayed a much lower increase in postprandial intact and total GLP-1 levels than controls. The increase in postprandial intact GLP-1 in HF patients correlated negatively with serum brain natriuretic peptide levels and DPP4 activity and positively with the glomerular filtration rate. Likewise, the postprandial increases in both intact and total GLP-1 were blunted in HF rats and were restored by DPP4 inhibition. Additionally, vehicle-treated HF rats displayed glucose intolerance and hyperinsulinemia, whereas normal glucose homeostasis was observed in vildagliptin-treated HF rats. We conclude that the postprandial increase in GLP-1 is blunted in non-diabetic HF. Impaired GLP-1 bioavailability after meal intake correlates with poor prognostic factors and may contribute to the establishment of a vicious cycle between glucose disturbance and HF development and progression.

Assuntos

Glicemia/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insuficiência Cardíaca/etiologia , Período Pós-Prandial/fisiologia , Idoso , Animais , Peptídeo C/sangue , Feminino , Intolerância à Glucose/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/fisiopatologia , Fragmentos de Peptídeos/sangue , Ratos Wistar

Assuntos

Fumar Cigarros , Hipertensão , Poluição por Fumaça de Tabaco , Animais , Atenolol , Pressão Sanguínea , Epinefrina , Felipressina , Ratos

RESUMO

Among the mechanisms of action of hyperbaric oxygenation (HBO), the chance of reducing injury by interfering with the mechanisms of redox homeostasis in the heart leads to the possibility of extending the period of viability of the myocardium at risk. This would benefit late interventions for reperfusion to the ischemic area. The objective of the present study was to investigate the changes in the redox system associated with HBO therapy maintained during the first hour after coronary occlusion in an acute myocardial infarction (MI) rat model. Surviving male rats (n=105) were randomly assigned to one of three groups: Sham (SH=26), myocardial infarction (MI=45) and infarction+hyperbaric therapy (HBO=34, 1 h at 2.5 atm). After 90 min of coronary occlusion, a sample of the heart was collected for western blot analysis of total protein levels of superoxide dismutase, catalase, peroxiredoxin and 3­nitrotyrosine. Glutathione was measured by enzyme­linked immunosorbent assay (ELISA). The detection of the superoxide radical anion was carried out by oxidation of dihydroethidium analyzed with confocal microscopy. The mortality rate of the MI group was significantly higher than that of the HBO group. No difference was noted in the myocardial infarction size. The oxidized/reduced glutathione ratio and peroxiredoxin were significantly higher in the SH and MI when compared to the HBO group. Superoxide dismutase enzymes and catalase were significantly higher in the HBO group compared to the MI and SH groups. 3­Nitrotyrosine and the superoxide radical were significantly lower in the HBO group compared to these in the MI and SH groups. These data demonstrated that hyperbaric oxygenation therapy decreased mortality by improving redox control in the hearts of rats in the acute phase of myocardial infarction.

Assuntos

Oclusão Coronária/terapia , Oxigenoterapia Hiperbárica , Infarto do Miocárdio/terapia , Animais , Catalase/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Masculino , Infarto do Miocárdio/mortalidade , Miocárdio/metabolismo , Oxirredução , Distribuição Aleatória , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo

Assuntos

Animais , Ratos , Poluição por Fumaça de Tabaco , Fumar Cigarros , Hipertensão , Atenolol , Pressão Sanguínea , Epinefrina , Felipressina

RESUMO

We previously showed that digitoxin prolongs the survival of rats with heart failure due to myocardial infarction (MI). In this study, we evaluated the effect of digitoxin on myocardial structure, ventricular function, and proteins involved in calcium kinetics. Seventy-two rats with MI >35% of the left ventricle were randomly assigned to 4 treatment groups: sham (n = 15), digitoxin (n = 11), infarction (n = 20), and infarction + digitoxin (n = 26). The rats were assessed 120 days after surgery by echocardiogram, hemodynamics, papillary muscle mechanics, collagen content, cardiomyocyte nuclear volume, and Western blot analysis of proteins involved in calcium kinetics. Digitoxin was administered via the rat chow. Two-way analysis of variance was used for comparisons. Myocardial infarction caused inotropic impairment, pulmonary congestion, increase of nuclear volume, myocardial collagen, and Na+/Ca2+ exchanger levels, and decreased SERCA2 and phosphorylated phospholamban levels. Treatment with digitoxin showed improvements in cardiac remodeling, inotropism, ventricular performance, pulmonary congestion, collagen accumulation, nuclear volume, and proteins involved in calcium kinetics. In rats with heart failure due to MI, long-term treatment with digitoxin attenuates congestive heart failure, mitigates myocardial remodeling and contractile impairment, and preserves myocardial levels of proteins involved in calcium kinetics.

Assuntos

Proteínas de Ligação ao Cálcio/metabolismo , Cardiotônicos/farmacologia , Digitoxina/farmacologia , Insuficiência Cardíaca/prevenção & controle , Hipertrofia Ventricular Esquerda/prevenção & controle , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Cálcio/metabolismo , Sinalização do Cálcio , Modelos Animais de Doenças , Feminino , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Cinética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Ratos Wistar

RESUMO

The present study aimed to analyze the effects of reperfusion of a distant coronary artery on cardiac function, the ultrastructure, and the molecular environment of the remote myocardium immediately after the completion of myocardial regional necrosis: delayed reperfusion (DR). Additionally, the effects of prior exercise on the outcomes of DR were investigated. Female rats with permanent occlusion or delayed reperfusion were randomly assigned to an exercise (swimming, 1 h/day, 5 days/week for 8 weeks) or sedentary protocol. Thus, the study included the following four groups: sedentary permanent occlusion, exercise permanent occlusion, sedentary delayed reperfusion, and exercise delayed reperfusion. The descending coronary artery was occluded for 1 h. Reperfusion was confirmed by contrast echocardiography, and the rats were observed for 4 weeks. Permanent occlusion and DR caused similar myocardial infarction sizes among the four groups. Interestingly, exercise significantly decreased the mortality rate. Delayed reperfusion resulted in significant benefits, including enhanced hemodynamics and papillary muscle contraction, as well as reduced apoptosis and collagen content. Protein calcium kinetics did not change. Meanwhile, developed tension and the Frank-Starling mechanism were enhanced, suggesting that calcium sensitivity was intensified in myofilaments. Remarkable remote myocardial benefits occurred after distant DR, and prior exercise intensified cardiac recovery. Our findings provide valuable information about DR. Our data might explain the better clinical outcomes in recent studies showing that late reperfusion could improve heart failure in patients with myocardial infarction. In conclusion, DR has remote myocardial benefits, including inotropism enhancement, pulmonary congestion reduction, and collagen and apoptosis attenuation, which are enhanced by prior exercise.

RESUMO

Low-level laser therapy (LLLT) has been targeted as a promising approach that can mitigate post-infarction cardiac remodeling. There is some interesting evidence showing that the beneficial role of the LLLT could persist long-term even after the end of the application, but it remains to be systematically evaluated. Therefore, the present study aimed to test the hypothesis that LLLT beneficial effects in the early post-infarction cardiac remodeling could remain in overt heart failure even with the disruption of irradiations. Female Wistar rats were subjected to the coronary occlusion to induce myocardial infarction or Sham operation. A single LLLT application was carried out after 60 s and 3 days post-coronary occlusion, respectively. Echocardiography was performed 3 days and at the end of the experiment (5 weeks) to evaluate cardiac function. After the last echocardiographic examination, LV hemodynamic evaluation was performed at baseline and on sudden afterload increases. Compared with the Sham group, infarcted rats showed increased systolic and diastolic internal diameter as well as a depressed shortening fraction of LV. The only benefit of the LLLT was a higher shortening fraction after 3 days of infarction. However, treated-LLLT rats show a lower shortening fraction in the 5th week of study when compared with Sham and non-irradiated rats. A worsening of cardiac function was confirmed in the hemodynamic analysis as evidenced by the higher LV end-diastolic pressure and lower +dP/dt and -dP/dt with five weeks of study. Cardiac functional reserve was also impaired by infarction as evidenced by an attenuated response of stroke work index and cardiac output to a sudden afterload stress, without LLLT repercussions. No significant differences were found in the myocardial expression of Akt1/VEGF pathway. Collectively, these findings illustrate that LLLT improves LV systolic function in the early post-infarction cardiac remodeling. However, this beneficial effect may be dependent on the maintenance of phototherapy. Long-term studies with LLLT application are needed to establish whether these effects ultimately translate into improved cardiac remodeling.