In the eukaryotic cell an intrinsic mechanism is present providing the ability to defend itself against external stressors from various sources. This defense mechanism probably evolved from the presence of a group of chaperones, playing a crucial role in governing proper protein assembly, folding, and transport. Upregulation of the synthesis of a number of these proteins upon environmental stress establishes a unique defense system to maintain cellular protein homeostasis and to ensure survival of the cell. In the cardiovascular system this enhanced protein synthesis leads to a transient but powerful increase in tolerance to such endangering situations as ischemia, hypoxia, oxidative injury, and endotoxemia. These so-called heat shock proteins interfere with several physiological processes within several cell organelles and, for proper functioning, are translocated to different compartments following stress-induced synthesis. In this review we describe the physiological role of heat shock proteins and discuss their protective potential against various stress agents in the cardiovascular system.

In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) cause blindness by neovascularization and subsequent fibrosis, but their relative contribution to both processes is unknown. We hypothesize that the balance between levels of pro-angiogenic VEGF and pro-fibrotic CTGF regulates angiogenesis, the angio-fibrotic switch, and the resulting fibrosis and scarring. VEGF and CTGF were measured by ELISA in 68 vitreous samples of patients with proliferative DR (PDR, N = 32), macular hole (N = 13) or macular pucker (N = 23) and were related to clinical data, including degree of intra-ocular neovascularization and fibrosis. In addition, clinical cases of PDR (n = 4) were studied before and after pan-retinal photocoagulation and intra-vitreal injections with bevacizumab, an antibody against VEGF. Neovascularization and fibrosis in various degrees occurred almost exclusively in PDR patients. In PDR patients, vitreous CTGF levels were significantly associated with degree of fibrosis and with VEGF levels, but not with neovascularization, whereas VEGF levels were associated only with neovascularization. The ratio of CTGF and VEGF was the strongest predictor of degree of fibrosis. As predicted by these findings, patients with PDR demonstrated a temporary increase in intra-ocular fibrosis after anti-VEGF treatment or laser treatment. CTGF is primarily a pro-fibrotic factor in the eye, and a shift in the balance between CTGF and VEGF is associated with the switch from angiogenesis to fibrosis in proliferative retinopathy.

Piezo1 is a mechanosensitive cation channel with widespread physiological importance; however, its role in the heart is poorly understood. Cardiac fibroblasts help preserve myocardial integrity and play a key role in regulating its repair and remodeling following stress or injury. Here, we investigated Piezo1 expression and function in cultured human and mouse cardiac fibroblasts. RT-PCR experiments confirmed that Piezo1 mRNA in cardiac fibroblasts is expressed at levels similar to those in endothelial cells. Results from the Fura-2 intracellular Ca²⁺ assay validated Piezo1 as a functional ion channel that is activated by its agonist, Yoda1. Yoda1-induced Ca²⁺ entry was inhibited by Piezo1 blockers (gadolinium and ruthenium red) and was reduced proportionally by siRNA-mediated Piezo1 knockdown or in murine Piezo1^+/- cells. Results from cell-attached patch-clamp recordings on human cardiac fibroblasts established that they contain mechanically activated ion channels and that their pressure responses are reduced by the Piezo1 knockdown. Investigation of Yoda1 effects on selected remodeling genes indicated that Piezo1 activation increases both mRNA levels and protein secretion of interleukin-6 (IL-6), a pro-hypertrophic and profibrotic cytokine, in a Piezo1-dependent manner. Moreover, Piezo1 knockdown reduced basal IL-6 expression from cells cultured on collagen-coated softer substrates. Multiplex kinase activity profiling, combined with kinase inhibitor experiments and phospho-specific immunoblotting, established that Piezo1 activation stimulates IL-6 secretion via the p38 mitogen-activated protein kinase downstream of Ca²⁺ entry. In summary, cardiac fibroblasts express mechanically activated Piezo1 channels coupled to secretion of the paracrine signaling molecule IL-6. Piezo1 may therefore be important in regulating cardiac remodeling.

Background Myoglobin and fatty acid–binding protein (FABP) each are useful as early biochemical markers of muscle injury. We studied whether the ratio of myoglobin over FABP in plasma can be used to distinguish myocardial from skeletal muscle injury. Methods and Results Myoglobin and FABP were assayed immunochemically in tissue samples of human heart and skeletal muscle and in serial plasma samples from 22 patients with acute myocardial infarction (AMI), from 9 patients undergoing aortic surgery (causing injury of skeletal muscles), and from 10 patients undergoing cardiac surgery. In human heart tissue, the myoglobin/FABP ratio was 4.5 and in skeletal muscles varied from 21 to 73. After AMI, the plasma concentrations of both proteins were elevated between ≈1 and 15 to 20 hours after the onset of symptoms. In this period, the myoglobin/FABP ratio was constant both in subgroups of patients receiving and those not receiving thrombolytics and amounted to 5.3±1.2 (SD). In serum from aortic surgery patients, both proteins were elevated between 6 and 24 hours after surgery; the myoglobin/FABP ratio was 45±22 (SD), which is significantly different from plasma values in AMI patients ( P <.001). In patients with cardiac surgery, the ratio increased from 11.3±4.7 to 32.1±13.6 (SD) during 24 hours after surgery, indicating more rapid release of protein from injured myocardium than from skeletal muscles. Conclusions The ratio of the concentrations of myoglobin over FABP in plasma from patients with muscle injury reflects the ratio found in the affected tissue. Since this ratio is different between heart (4.5) and skeletal muscle (20 to 70), its assessment in plasma allows the discrimination between myocardial and skeletal muscle injury in humans.

The failing heart is characterized by alterations in energy metabolism, including mitochondrial dysfunction and a reduction in fatty acid (FA) oxidation rate, which is partially compensated by an increase in glucose utilization. Together, these changes lead to an impaired capacity to convert chemical energy into mechanical work. This has led to the concept that supporting cardiac energy conversion through metabolic interventions provides an important adjuvant therapy for heart failure. The potential success of such a therapy depends on whether the shift from FA towards glucose utilization should be considered beneficial or detrimental, a question still incompletely resolved. In this review, the current status of the literature is evaluated and possible causes of observed discrepancies are discussed. It is cautiously concluded that for the failing heart, from a therapeutic point of view, it is preferable to further stimulate glucose oxidation rather than to normalize substrate metabolism by stimulating FA utilization. Whether this also applies to the pre-stages of cardiac failure remains to be established.