Pharmacological myeloperoxidase (MPO) inhibition in an obese/hypertensive mouse model attenuates obesity and liver damage, but not cardiac remodeling.

Lifestyle factors are important drivers of chronic diseases, including cardiovascular syndromes, with low grade inflammation as a central player. Attenuating myeloperoxidase (MPO) activity, an inflammatory enzyme associated with obesity, hypertension and heart failure, could have protective effects on multiple organs. Herein, the effects of the novel oral available MPO inhibitor AZM198 were studied in an obese/hypertensive mouse model which displays a cardiac phenotype. Eight week old male C57BL6/J mice received 16 weeks of high fat diet (HFD) combined with angiotensin II (AngII) infusion during the last 4 weeks, with low fat diet and saline infusion as control. Treated animals showed therapeutic AZM198 levels (2.1 µM), corresponding to 95% MPO inhibition. AZM198 reduced elevated circulating MPO levels in HFD/AngII mice to normal values. Independent of food intake, bodyweight increase and fat accumulation were attenuated by AZM198, alongside with reduced visceral adipose tissue (VAT) inflammation and attenuated severity of nonalcoholic steatohepatitis. The HFD/AngII perturbation caused impaired cardiac relaxation and contraction, and increased cardiac hypertrophy and fibrosis. AZM198 treatment did, however, not improve these cardiac parameters. Thus, AZM198 had positive effects on the main lipid controlling tissues in the body, namely adipose tissue and liver. This did, however, not directly result in improved cardiac function.

Sodium-glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction.

AIMS: Sodium-glucose co-transporter 2 (SGLT2) inhibition reduces heart failure hospitalizations in patients with diabetes, irrespective of glycaemic control. We examined the effect of SGLT2 inhibition with empagliflozin (EMPA) on cardiac function in non-diabetic rats with left ventricular (LV) dysfunction after myocardial infarction (MI). METHODS AND RESULTS: Non-diabetic male Sprague-Dawley rats underwent permanent coronary artery ligation to induce MI, or sham surgery. Rats received chow containing EMPA that resulted in an average daily intake of 30 mg/kg/day or control chow, starting before surgery (EMPA-early) or 2 weeks after surgery (EMPA-late). Cardiac function was assessed using echocardiography and histological and molecular markers of cardiac remodelling and metabolism were assessed in the left ventricle. Renal function was assessed in metabolic cages. EMPA increased urine production by two-fold without affecting creatinine clearance and serum electrolytes. EMPA did not influence MI size, but LV ejection fraction (LVEF) was significantly higher in the EMPA-early and EMPA-late treated MI groups compared to the MI group treated with vehicle (LVEF 54%, 52% and 43%, respectively, all P < 0.05). EMPA also attenuated cardiomyocyte hypertrophy, diminished interstitial fibrosis and reduced myocardial oxidative stress. EMPA treatment reduced mitochondrial DNA damage and stimulated mitochondrial biogenesis, which was associated with the normalization of myocardial uptake and oxidation of glucose and fatty acids. EMPA increased circulating ketone levels as well as myocardial expression of the ketone body transporter and two critical ketogenic enzymes, indicating that myocardial utilization of ketone bodies was increased. Together these metabolic changes were associated with an increase in cardiac ATP production. CONCLUSION: Empagliflozin favourably affects cardiac function and remodelling in non-diabetic rats with LV dysfunction after MI, associated with substantial improvements in cardiac metabolism and cardiac ATP production. Importantly, it did so without renal adverse effects. Our data suggest that EMPA might be of benefit in heart failure patients without diabetes.

OPLAH ablation leads to accumulation of 5-oxoproline, oxidative stress, fibrosis, and elevated fillings pressures: a murine model for heart failure with a preserved ejection fraction.

Aims: The prevalence of heart failure with a preserved ejection fraction (HFpEF) is increasing, but therapeutic options are limited. Oxidative stress is suggested to play an important role in the pathophysiology of HFpEF. However, whether oxidative stress is a bystander due to comorbidities or causative in itself remains unknown. Recent results have shown that depletion of 5-oxoprolinase (OPLAH) leads to 5-oxoproline accumulation, which is an important mediator of oxidative stress in the heart. We hypothesize that oxidative stress induced by elevated levels of 5-oxoproline leads to the onset of a murine HFpEF-like phenotype. Methods and results: Oplah full body knock-out (KO) mice had higher 5-oxoproline levels coupled to increased oxidative stress. Compared with wild-type (WT) littermates, KO mice had increased cardiac and renal fibrosis with concurrent elevated left ventricular (LV) filling pressures, impaired LV relaxation, yet a normal LV ejection fraction. Following the induction of cardiac ischaemia/reperfusion (IR) injury, 52.4% of the KO mice died compared with only 15.4% of the WT mice (P < 0.03). Furthermore, KO mice showed a significantly increased atrial, ventricular, kidney, and liver weights compared with WT mice (P < 0.05 for all). Cardiac and renal fibrosis were more pronounced following cardiac IR injury in the KO mice and these mice developed proteinuria post-IR injury. To further address the link between 5-oxoproline and HFpEF, 5-oxoproline was measured in the plasma of HFpEF patients. Compared with healthy controls (3.8 ± 0.6 µM), 5-oxoproline levels were significantly elevated in HFpEF patients (6.8 ± 1.9 µM, P < 0.0001). Furthermore, levels of 5-oxoproline were independently associated with more concentric remodelling on echocardiography. Conclusion: Oxidative stress induced by 5-oxoproline results in a murine phenotype reminiscent of the clinical manifestation of HFpEF without the need for surgical or pharmacological interference. Better understanding of the role of oxidative stress in HFpEF may potentially lead to novel therapeutic options.