Preservation of myocardial fatty acid oxidation prevents diastolic dysfunction in mice subjected to angiotensin II infusion

Abstract

Rationale Diastolic dysfunction is a common feature in many heart failure patients with preserved ejection fraction and has been associated with altered myocardial metabolism in hypertensive and diabetic patients. Therefore, metabolic interventions to improve diastolic function are warranted. In mice with a germline cardiac-specific deletion of acetyl CoA carboxylase 2 (ACC2), systolic dysfunction induced by pressure-overload was prevented by maintaining cardiac fatty acid oxidation (FAO). However, it has not been evaluated whether this strategy would prevent the development of diastolic dysfunction in the adult heart. Objective To test the hypothesis that augmenting cardiac FAO is protective against angiotensin II (AngII)-induced diastolic dysfunction in an adult mouse heart. Methods and Results We generated a mouse model to induce cardiac-specific deletion of ACC2 in adult mice. Tamoxifen treatment (20mg/kg/day for 5 days) was sufficient to delete ACC2 protein and increase cardiac FAO by 50% in ACC2 flox/flox-MerCreMer+ mice (iKO). After 4 weeks of AngII (1.1mg/kg/day), delivered by osmotic mini-pumps, iKO mice showed normalized E/E′ and E′/A′ ratios compared to AngII treated controls (CON). The prevention of diastolic dysfunction in iKO-AngII was accompanied by maintained FAO and reduced glycolysis and anaplerosis. Furthermore, iKO-AngII hearts had a ~50% attenuation of cardiac hypertrophy and fibrosis compared to CON. In addition, maintenance of FAO in iKO hearts suppressed AngII-associated increases in oxidative stress and sustained mitochondrial respiratory complex activities. Conclusion These data demonstrate that impaired FAO is a contributor to the development of diastolic dysfunction induced by AngII. Maintenance of FAO in this model leads to an attenuation of hypertrophy, reduces fibrosis, suppresses increases in oxidative stress, and maintains mitochondrial function. Therefore, targeting mitochondrial FAO is a promising therapeutic strategy for the treatment of diastolic dysfunction.

Blockade of PDGF Receptors by Crenolanib Has Therapeutic Effect in Patient Fibroblasts and in Preclinical Models of Systemic Sclerosis

“…As reported before, mice challenged with Ang II develop heart fibrosis (Choi et al, 2016). Crenolanib treatment significantly reduced heart fibrosis as determined by picrosirius red-positive area per total area (Figure 6a and b).…”

Serum uric acid is associated with incidence of heart failure with preserved ejection fraction and cardiovascular events in patients with arterial hypertension

“…Furthermore, increased activity of this enzyme, which is involved in the reaction of hypoxanthine and xanthine to UA, causes the release of free radicals and increased oxidative stress. Oxidative stress also contributes to the pathogenesis of HFpEF . Several studies have previously examined whether UA‐lowering therapy with xanthine oxidase inhibitor allopurinol or oxypurinol leads to clinical and functional improvement of HF; however, the results are not consistent .…”

“…Oxidative stress also contributes to the pathogenesis of HFpEF. 24,25 Several studies have previously examined whether UA-lowering therapy with xanthine oxidase inhibitor allopurinol or oxypurinol leads to clinical and functional improvement of HF; however, the results are not consistent. [26][27][28][29][30] Cingolani and colleagues 26 indicated that inhibition of xanthine oxidase by oxypurinol in patients with chronic HF decreased UA level and improved LVEF in patients with LVEF ≤40% after 1 month of treatment.…”

The effects of fatty acid composition on cardiac hypertrophy and function in mouse models of diet-induced obesity

“…M-mode image sequences and Tissue Doppler imaging (TDI) was performed on the Vevo 2100 High-Resolution Imaging System (VisualSonics, Toronto, Ontario, Canada) with a MS400 MicroScan Transducer, centered at 30 MHz [13, 14]. …”