Rationale: Excessive Ang II (angiotensin II) levels lead to a profibrotic and hypertrophic milieu that produces deleterious remodeling and dysfunction in hypertension-associated heart failure. Agents that disrupt Ang II–induced cardiac dysfunction may have clinical utility in the treatment of hypertension-associated heart failure. Objective: We have examined the potential effect of celastrol—a bioactive compound derived from the Celastraceae family—on Ang II–induced cardiac dysfunction. Methods and Results: In rat primary cardiomyocytes and H9C2 (rat cardiomyocyte-like H9C2) cells, celastrol attenuates Ang II–induced cellular hypertrophy and fibrotic responses. Proteome microarrays, surface plasmon resonance, competitive binding assays, and molecular simulation were used to identify the molecular target of celastrol. Our data showed that celastrol directly binds to and inhibits STAT (signal transducer and activator of transcription)-3 phosphorylation and nuclear translocation. Functional tests demonstrated that the protection of celastrol is afforded through targeting STAT3. Overexpression of STAT3 dampens the effect of celastrol by partially rescuing STAT3 activity. Finally, we investigated the in vivo effect of celastrol treatment in mice challenged with Ang II and in the transverse aortic constriction model. We show that celastrol administration protected heart function in Ang II–challenged and transverse aortic constriction–challenged mice by inhibiting cardiac fibrosis and hypertrophy. Conclusions: Our studies show that celastrol inhibits Ang II–induced cardiac dysfunction by inhibiting STAT3 activity.

Hyperglycemia activates toll-like receptor 4 (TLR4) to induce inflammation in diabetic cardiomyopathy (DCM). However, the mechanisms of TLR4 activation remain unclear. Here we examine the role of myeloid differentiation 2 (MD2), a co-receptor of TLR4, in high glucose (HG)-and diabetes-induced inflammatory cardiomyopathy. We show increased MD2 in heart tissues of diabetic mice and serum of human diabetic subjects. MD2 deficiency in mice inhibits TLR4 pathway activation, which correlates with reduced myocardial remodeling and improved cardiac function. Mechanistically, we show that HG induces extracellular advanced glycation end products (AGEs), which bind directly to MD2, leading to formation of AGEs-MD2-TLR4 complex and initiation of pro-inflammatory pathways. We further detect elevated AGE-MD2 complexes in heart tissues and serum of diabetic mice and human subjects with DCM. In summary, we uncover a new mechanism of HG-induced inflammatory responses and myocardial injury, in which AGE products directly bind MD2 to drive inflammatory DCM.

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Modern lifestyles have altered diet and metabolic homeostasis, with increased sugar intake, glycemic index, and prediabetes. A strong positive correlation between sugar consumption and diabetic incidence is revealed, but the underlying mechanisms remain obscure. Here we show that oral intake of long-term oscillating glucose (LOsG) (4 times/day) for 38 days, which produces physiological glycemic variability in rats, can lead to β-cells gaining metabolic memory in reactive oxygen species (ROS) stress. This stress leads to suppression of forkhead box O1 (FoxO1) signaling and subsequent upregulation of thioredoxin interacting protein, inhibition of insulin and SOD-2 expression, re-expression of Neurog3, and β-cell dedifferentiation and functional failure. LOsG-treated animals develop prediabetes exhibiting hypoinsulinemia and glucose intolerance. Dynamic and timely administration of antioxidant glutathione prevents LOsG/ROS-induced β-cell failure and prediabetes. We propose that ROS stress is the initial step in LOsG-inducing prediabetes. Manipulating glutathione-related pathways may offer novel options for preventing the occurrence and development of diabetes.

The innate immune system contains multiple classes of pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the intracellular and extracellular space. Although PRRs are indispensable for the detection and clearance of invading pathogens, dysregulated PRR activation by extrinsic and intrinsic factors leads to inflammatory diseases. PRRmediated inflammation has been shown to play a pivotal role in the pathogenesis of diabetic vascular complications (DVCs), which are the leading causes of morbidity and mortality in diabetic patients. Upon sensing hyperglycemiagenerated DAMPs, PRRs activate intracellular signaling pathways leading to the production of proinflammatory cytokines and chemokines in various cells of the kidney, brain, eye, and heart. The resulting chronic, low-grade inflammation contributes to DVCs. In this review, we summarize the role of PRRs in DVCs including diabetic nephropathy, neuropathy, retinopathy, and cardiomyopathy. We propose that targeting PRRs and associated signaling pathways may be beneficial for the management of DVCs.