Mitochondrial fatty acid oxidation is the major source of cardiac adenosine triphosphate production in heart failure with preserved ejection fraction.

Aims: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disease worldwide. While it is well established that alterations of cardiac energy metabolism contribute to cardiovascular pathology, the precise source of fuel used by the heart in HFpEF remains unclear. The objective of this study was to define the energy metabolic profile of the heart in HFpEF.

Obesity Is a Major Determinant of Impaired Cardiac Energy Metabolism in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a major health problem with limited treatment options. Although optimizing cardiac energy metabolism is a potential approach to treating heart failure, it is poorly understood what alterations in cardiac energy metabolism actually occur in HFpEF. To determine this, we used mice in which HFpEF was induced using an obesity and hypertension HFpEF protocol for 10 weeks.

HSP70: From Signaling Mechanisms to Therapeutics.

Heat-shock proteins (HSPs) are primary stress responders that are vital to maintaining homeostasis [...

Increased eHSP70-to-iHSP70 ratio disrupts vascular responses to calcium and activates the TLR4-MD2 complex in type 1 diabetes.

Aims: Vascular dysfunction is a clinical hallmark of diabetes. While various pathways drive vascular alterations in diabetes, many gaps persist in understanding this process. Heat-shock protein 70 (HSP70) has a long-recognized role in diabetes, but the contributions of HSP70 to the diabetic vasculature remain largely unknown.

New insights into the role and therapeutic potential of HSP70 in diabetes.

Emerging evidence indicates that HSP70 represents a key mechanism in the pathophysiology of β-cell dysfunction, insulin resistance, and various diabetic complications, including micro- and macro-vascular alterations, as well as impaired hemostasis. Hyperglycemia, a hallmark of both types of diabetes, increases the circulating levels of HSP70 (eHSP70), but there is still divergence about whether diabetes up- or down-regulates the intracellular fraction of this protein (iHSP70). Here, we consider that iHSP70 levels reduce in diabetic arterial structures and that the vascular system is in direct contact with all other systems in the body suggesting that a systemic response might also be happening for iHSP70, which is characterized by decreased levels of HSP70 in the vasculature.

Crosstalk of TLR4, vascular NADPH oxidase, and COVID-19 in diabetes: What are the potential implications?

Toll-like receptor 4 (TLR4) contributes to the pathophysiology of diabetes. This happens, at least in part, because TLR4 modulates the enzyme NADPH oxidase, a primary source of ROS in vascular structures. Increased oxidative stress disrupts key vascular signaling mechanisms and drives the progression of diabetes, elevating the likelihood of cardiovascular diseases.

Impaired HSP70 Expression in the Aorta of Female Rats: A Novel Insight Into Sex-Specific Differences in Vascular Function.

Heat-shock protein 70 (HSP70) contributes to cellular calcium (Ca) handling mechanisms during receptor-mediated vascular contraction. Interestingly, previous studies have independently reported sex-related differences in HSP70 expression and Ca dynamics. Still, it is unknown if sex, as a variable, plays a role in the impact that HSP70 has upon vascular contraction.

Hypertension and Erectile Dysfunction: Breaking Down the Challenges.

A diagnostic of hypertension increases the risk of erectile dysfunction (ED); likewise, ED can be an early sign of hypertension. In both cases, there is evidence that endothelial dysfunction is a common link between the 2 conditions. During hypertension, the sustained and widespread release of procontractile factors (e.

Blockade of the TLR4-MD2 complex lowers blood pressure and improves vascular function in a murine model of type 1 diabetes.

While the pathogenesis of diabetes-induced high blood pressure (BP) is not entirely clear, current evidence suggests that Toll-like receptor 4 (TLR4) is a key player in the mechanisms associated with hypertension. However, it is unknown whether this receptor affects BP under type 1 diabetes. Likewise, there is insufficient knowledge about the role of TLR4 in diabetes-associated vascular dysfunction of large arteries.

An additional physiological role for HSP70: Assistance of vascular reactivity.

Aims: HSP70, a molecular chaperone, helps to maintain proteostasis. In muscle biology, however, evidence suggests HSP70 to have a more versatile range of functions, as genetic deletion of its inducible genes impairs Ca handling, and consequently, cardiac and skeletal muscle contractility. Still, it is unknown whether HSP70 is involved in vascular reactivity, an intrinsic physiological mechanism of blood vessels.

Blockade of Toll-like receptor 4 (TLR4) reduces oxidative stress and restores phospho-ERK1/2 levels in Leydig cells exposed to high glucose.

Aims: Hyperglycemia in combination with oxidative stress plays a significant pathophysiological role in diabetic testicular dysfunction, often leading to infertility. Activation of Toll-like receptor 4 (TLR4) has been reported to mediate oxidative stress during diabetes. However, engagement of the TLR4 signaling pathway in diabetic testicular dysfunction has not been previously explored.

Pattern recognition receptors as potential therapeutic targets in metabolic syndrome: From bench to bedside.

Pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) play crucial roles in the underlying mechanisms of metabolic syndrome (MetS). Mainly, these receptors have been suggested to participate in the pathophysiological processes involved in the complications associated with this condition. Therefore, to evolve therapeutic strategies targeting PRRs might be an imperative approach to avoid the development of further complications in human subjects.

Unveiling the Interplay between the TLR4/MD2 Complex and HSP70 in the Human Cardiovascular System: A Computational Approach.

While precise mechanisms underlying cardiovascular diseases (CVDs) are still not fully understood, previous studies suggest that the innate immune system, through Toll-like receptor 4 (TLR4), plays a crucial part in the pathways leading to these diseases, mainly because of its interplay with endogenous molecules. The Heat-shock protein 70 family (HSP70-70kDa) is of particular interest in cardiovascular tissues as it may have dual effects when interacting with TLR4 pathways. Although the hypothesis of the HSP70 family members acting as TLR4 ligands is becoming widely accepted, to date no co-crystal structure of this complex is available and it is still unknown whether this process requires the co-adaptor MD2.

Toll-like receptor 4 (TLR4) as a possible pathological mechanism in hyperglycemia-associated testicular dysfunction.

Hyperglycemia is a chief factor in diabetes, a complex disease associated with reproductive disorders, mainly testicular dysfunction, which contributes to male infertility. Leydig cells are the predominant cell population in the testis interstitium and, when stimulated, they are capable of initiating immune responses playing crucial roles in the mechanisms related to testis' homeostasis. These cells express TLR4, an innate immune receptor, which is known to be modulated by hyperglycemia in other cell populations and tissue types.

Blockade of Toll-Like Receptor 4 Attenuates Erectile Dysfunction in Diabetic Rats.

Introduction: While increased toll-like receptor (TLR)4 activity may contribute to the pathophysiology of vascular diseases, the molecular mechanisms disrupted by this receptor in the vasculature are still poorly understood. Additionally, it is unknown if TLR4 mediates erectile dysfunction (ED) during diabetes.

Aim: To investigate whether pharmacological blockade of TLR4 affects erectile function in a murine model of diabetes.

Toll-Like Receptor 4 and Heat-Shock Protein 70: Is it a New Target Pathway for Diabetic Vasculopathies?

Diabetes is one of the most concerning diseases in modern times. Despite considerable advances in therapeutic management, the prevalence of diabetes and its contribution to death and disability continue to be a major health problem. Diabetic vasculopathies are the leading cause of mortality and morbidity in diabetic patients.

Targeting toll-like receptor 4 signalling pathways: can therapeutics pay the toll for hypertension?

The immune system plays a prominent role in the initiation and maintenance of hypertension. The innate immune system, via toll-like receptors (TLRs), identifies distinct signatures of invading microbes and damage-associated molecular patterns and triggers a chain of downstream signalling cascades, leading to secretion of pro-inflammatory cytokines and shaping the adaptive immune response. Over the past decade, a dysfunctional TLR-mediated response, particularly via TLR4, has been suggested to support a chronic inflammatory state in hypertension, inducing deleterious local and systemic effects in host cells and tissues and contributing to disease progression.