Increasing evidence indicates that mitochondrial-associated redox signaling contributes to the pathophysiology of heart failure (HF). The mitochondrial-targeted antioxidant, mitoquinone (MitoQ), is capable of modifying mitochondrial signaling and has shown beneficial effects on HF-dependent mitochondrial dysfunction. However, the potential therapeutic impact of MitoQ-based mitochondrial therapies for HF in response to pressure overload is reliant upon demonstration of improved cardiac contractile function and suppression of deleterious cardiac remodeling. Using a new (patho)physiologically relevant model of pressure overload-induced HF we tested the hypothesis that MitoQ is capable of ameliorating cardiac contractile dysfunction and suppressing fibrosis. To test this C57BL/6J mice were subjected to left ventricular (LV) pressure overload by ascending aortic constriction (AAC) followed by MitoQ treatment (2 µmol) for 7 consecutive days. Doppler echocardiography showed that AAC caused severe LV dysfunction and hypertrophic remodeling. MitoQ attenuated pressure overload-induced apoptosis, hypertrophic remodeling, fibrosis and LV dysfunction. Profibrogenic transforming growth factor-β1 (TGF-β1) and NADPH oxidase 4 (NOX4, a major modulator of fibrosis related redox signaling) expression increased markedly after AAC. MitoQ blunted TGF-β1 and NOX4 upregulation and the downstream ACC-dependent fibrotic gene expressions. In addition, MitoQ prevented Nrf2 downregulation and activation of TGF-β1-mediated profibrogenic signaling in cardiac fibroblasts (CF). Finally, MitoQ ameliorated the dysregulation of cardiac remodeling-associated long noncoding RNAs (lncRNAs) in AAC myocardium, phenylephrine-treated cardiomyocytes, and TGF-β1-treated CF. The present study demonstrates for the first time that MitoQ improves cardiac hypertrophic remodeling, fibrosis, LV dysfunction and dysregulation of lncRNAs in pressure overload hearts, by inhibiting the interplay between TGF-β1 and mitochondrial associated redox signaling.

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Induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) provide a human source of cardiomyocytes for use in cardiovascular research and regenerative medicine. However, attempts to use these cells in vivo have resulted in drastic cell death caused by mechanical, metabolic, and/or exogenous factors. To explore this issue, we designed a Biomimetic Cardiac Tissue Model (BCTM) where various parameters associated with heart function including heart rate, peak-systolic pressure, end-diastolic pressure and volume, end-systolic pressure and volume, and ratio of systole to diastole can all be precisely manipulated to apply hemodynamic loading to culture cells. Using the BCTM, two causes of low survivability in current cardiac stem cell therapies, mechanical and metabolic, were explored. iPSC-CMs were subject to physiologically relevant mechanical loading (50 mmHg systolic, 10% biaxial stretch) in either a low- or high-serum environment and mechanical loads were applied either immediately or gradually. Results confirm that iPSC-CMs subject to mechanical loading in low-serum conditions experienced widespread cell death. The rate of application of stress also played an important role in adaptability to mechanical loading. Under high-serum conditions, iPSC-CMs subject to gradual imposition of stress were comparable to iPSC-CMs maintained in static culture when evaluated in terms of cell viability, sarcomeric structure, action potentials and conduction velocities. In contrast, iPSC-CMs that were immediately exposed to mechanical loading had significantly lower cell viability, destruction of sarcomeres, smaller action potentials and lower conduction velocities. We report that iPSC-CMs survival under physiologically relevant hemodynamic stress requires gradual imposition of mechanical loads in a nutrient-rich environment.

Type 2 diabetes significantly elevates the risk of cardiovascular disease. This can be largely attributed to the adverse effects of hyperglycemic conditions on normal endothelial cell (EC) function. ECs in both large and small vessels are influenced by hyperglycemic conditions, which increase susceptibility to EC dysfunction and atherosclerotic lesion formation. Fluid shear stress and flow patterns play an essential role in atherogenesis: lesions form only at locations where fluid flow behavior can be classified as "disturbed flow" (i.e., low shear stress recirculation and/or retrograde flow). Since regions of disturbed flow are the focal points of atherosclerotic cardiovascular disease, we hypothesized that the combinatorial effects of high glucose and disturbed flow conditions elicit significantly different responses from ECs than high glucose alone. To validate our hypothesis, we used our endothelial cell culture model (ECCM) to establish vascular niches associated with "normal" and "disturbed" flow conditions typically seen in vivo along with physiological pressure and stretch. We subjected human aortic endothelial cells (HAECs) to hyperglycemic conditions under both "normal" and "disturbed" flow. Our results confirm significant and quantifiable differences in phenotypic and functional markers between cells cultured under conditions of "normal" and "disturbed flow" under hyperglycemic conditions suggesting that elevated glucose in conjunction with "disturbed" flow conditions results in significantly higher level of EC dysfunction. The ECCM can therefore be used as a physiologically relevant model to study early stage hyperglycemia induced atherosclerosis for basic research, drug discovery, and screening and toxicity studies.