Autophagy is a catalytic process of the bulk degradation of long-lived cellular components, ultimately resulting in lysosomal digestion within mature cytoplasmic compartments known as autophagolysosomes. Autophagy serves many functions in the cell, including maintaining cellular homeostasis, a means of cell survival during stress (e.g., nutrient deprivation or starvation) or conversely as a mechanism for cell death. Increased reactive oxygen species (ROS) production and the resulting oxidative cell stress that occurs in many disease states has been shown to induce autophagy. The following review focuses on the roles that autophagy plays in response to the ROS generated in several diseases.

oxygen species (ROS) induce matrix metalloproteinase (MMP) activity that mediates hypertrophy and cardiac remodeling. Adiponectin (APN), an adipokine, modulates cardiac hypertrophy, but it is unknown if APN inhibits ROS-induced cardiomyocyte remodeling. We tested the hypothesis that APN ameliorates ROS-induced cardiomyocyte remodeling and investigated the mechanisms involved. Cultured adult rat ventricular myocytes (ARVM) were pretreated with recombinant APN (30 g/ml, 18 h) followed by exposure to physiologic concentrations of H2O2 (1-200 M). ARVM hypertrophy was measured by [ 3 H]leucine incorporation and atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) gene expression by RT-PCR. MMP activity was assessed by in-gel zymography. ROS was induced with angiotensin (ANG)-II (3.2 mg·kg Ϫ1 ·day Ϫ1 for 14 days) in wild-type (WT) and APN-deficient (APN-KO) mice. Myocardial MMPs, tissue inhibitors of MMPs (TIMPs), p-AMPK, and p-ERK protein expression were determined. APN significantly decreased H2O2-induced cardiomyocyte hypertrophy by decreasing total protein, protein synthesis, ANF, and BNP expression. H2O2-induced MMP-9 and MMP-2 activities were also significantly diminished by APN. APN significantly increased p-AMPK in both nonstimulated and H2O2-treated ARVM. H 2O2-induced p-ERK activity and NF-B activity were both abrogated by APN pretreatment. ANG II significantly decreased myocardial p-AMPK and increased p-ERK expression in vivo in APN-KO vs. WT mice. ANG II infusion enhanced cardiac fibrosis and MMP-2-to-TIMP-2 and MMP-9-to-TIMP-1 ratios in APN-KO vs. WT mice. Thus APN inhibits ROS-induced cardiomyocyte remodeling by activating AMPK and inhibiting ERK signaling and NF-B activity. Its effects on ROS and ultimately on MMP expression define the protective role of APN against ROSinduced cardiac remodeling. reactive oxygen species; adenosine 5=-monophosphate-activated protein kinase; matrix metalloproteinase; cardiomyocyte hypertrophy

Diastolic heart failure (HF) i.e., “HF with preserved ejection fraction” (HF-preserved EF) accounts for up to 50% of all HF presentations; however there have been no therapeutic advances. This stems in part from an incomplete understanding about HF-preserved EF. Hypertension is the major cause of HF-preserved EF whilst HF-preserved EF is also highly associated with obesity. Similarly, excessive reactive oxygen species (ROS), i.e., oxidative stress occurs in hypertension and obesity, sensitizing the heart to the renin-angiotensin-aldosterone system, inducing autophagic type-II programmed cell death and accelerating the propensity to adverse cardiac remodeling, diastolic dysfunction and HF. Adiponectin (APN), an adipokine, mediates cardioprotective actions but it is unknown if APN modulates cardiomyocyte autophagy. We tested the hypothesis that APN ameliorates oxidative stress-induced autophagy in cardiomyocytes. Isolated adult rat ventricular myocytes were pretreated with recombinant APN (30µg/mL) followed by 1mM hydrogen peroxide (H2O2) exposure. Wild type (WT) and APN-deficient (APN-KO) mice were infused with angiotensin (Ang)-II (3.2mg/kg/d) for 14 days to induced oxidative stress. Autophagy-related proteins, mTOR, AMPK and ERK expression were measured. H2O2 induced LC3I to LC3II conversion by a factor of 3.4±1.0 which was abrogated by pre-treatment with APN by 44.5±10%. However, neither H2O2 nor APN affected ATG5, ATG7, or Beclin-1 expression. H2O2 increased phospho-AMPK by 49±6.0%, whilst pretreatment with APN decreased phospho-AMPK by 26±4%. H2O2 decreased phospho-mTOR by 36±13%, which was restored by APN. ERK inhibition demonstrated that the ERK-mTOR pathway is involved in H2O2-induced autophagy. Chronic Ang-II infusion significantly increased myocardial LC3II/I protein expression ratio in APN-KO vs. WT mice. These data suggest that excessive ROS caused cardiomyocyte autophagy which was ameliorated by APN by inhibiting an H2O2-induced AMPK/mTOR/ERK-dependent mechanism. These findings demonstrate the anti-oxidant potential of APN in oxidative stress-associated cardiovascular diseases, such as hypertension-induced HF-preserved EF.

Background-A new intracellular adenosine triphosphate (ATP) delivery technique has been developed and was tested for skin wound care.

Background Despite the increasing prevalence of heart failure (HF) with preserved ejection fraction (HFpEF) in humans, there remains no therapeutic options for HFpEF. Adiponectin (APN), an adipocyte-derived cytokine exerts cardioprotective actions and its deficiency is implicated in the development of hypertension and HF with reduced ejection fraction. Similarly APN deficiency in HFpEF exacerbates left ventricular hypertrophy (LVH), diastolic dysfunction and HF. However, the therapeutic effects of APN in HFpEF remain unknown. We sought to test the hypothesis that chronic APN overexpression protects against the progression of HF in a murine model of HFpEF. Methods and Results APN transgenic (APNTG) and wild-type (WT) mice underwent uninephrectomy, a continuous saline or d-aldosterone infusion and given 1.0% sodium chloride drinking water for 4-weeks. Aldosterone-infused WT mice developed HFpEF with hypertension, LVH and diastolic dysfunction. Aldosterone infusion increased myocardial oxidative stress and decreased sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) protein expression in HFpEF. Although total phospholamban (PLN) protein expression was unchanged, there was decreased expression of PKA-dependent PLN phosphorylation at Ser16 and CaMKII-dependent PLN phosphorylation at Thr17. APN overexpression in aldosterone-infused mice ameliorated LVH, diastolic dysfunction, lung congestion and myocardial oxidative stress without affecting blood pressure (BP) and LVEF. This improvement in diastolic function parameters in aldosterone-infused APNTG mice was accompanied by preserved protein expression of PKA-dependent phosphorylation of PLN at Ser16. APN replacement prevented the progression of aldosterone-induced HFpEF, independent of BP, by improving diastolic dysfunction and modulating cardiac hypertrophy. Conclusions These findings suggest that APN may have therapeutic effects in patients with HFpEF.