Myocardial fibrosis and apoptosis, but not inflammation, are present in long-term experimental diabetes

Abstract

The aim of this paper is to study the myocardial damage secondary to long-term streptozotocin-induced type 1 diabetes mellitus (DM1). Normotensive and spontaneously hypertensive rats (SHR) received either streptozotocin injections or vehicle. After 22 or 6 wk, DM1, SHR, DM1/SHR, and control rats were killed, and the left ventricles studied by histology, quantitative PCR, Western blot, ELISA, and electromobility shift assay. Cardiomyocyte cultures were also performed. The expression of profibrotic factors, transforming growth factor-beta (TGF-beta1), connective tissue growth factor, and matrix proteins was increased, and the TGF-beta1-linked transcription factors phospho-Smad3/4 and activator protein-1 were activated in the DM1 myocardium. Proapoptotic molecules FasL, Fas, Bax, and cleaved caspase-3 were also augmented. Myocardial injury in long-term hypertension shared these features. In addition, hypertension was associated with activation of NF-kappaB, increased inflammatory cell infiltrate, and expression of the mediators [interleukin-1beta (IL-1beta), tumor necrosis factor-alpha, monocyte chemoattractant protein 1, vascular cell adhesion molecule 1, angiotensinogen, and oxidants], which were absent in long-term DM1. At this stage, the combination of DM1 and hypertension resulted in nonsignificant additive effects. Moreover, the coexistence of DM1 blunted the inflammatory response to hypertension. Anti-inflammatory IL-10 and antioxidants were induced in long-term DM1 and DM1/SHR hearts. Myocardial inflammation was, however, observed in the short-term model. In cultured cardiomyocytes, IL-10, TGF-beta1, and catalase blocked the glucose-stimulated expression of proinflammatory genes. Fibrosis and apoptosis are features of long-term myocardial damage in experimental DM1. Associated hypertension does not induce additional changes. Myocardial inflammation is present in hypertension and short-term DM1, but is not a key feature in long-term DM1. Local reduction of proinflammatory factors and expression of anti-inflammatory and antioxidant molecules may underlie this effect.

Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro

“…The activation of NF-κB, which is downstream of mitogen-activated protein kinases, has also been shown to participate in several physiological processes in cardiac fibroblasts [27] . The activation of ERK1/2 and NF-κB has been shown to be involved in collagen deposition in the hearts of diabetic and hypertensive animals [28][29][30][31] . Ang II and glucose-induced collagen accumulation in the cultured cardiac fibroblasts has also been demonstrated to involve the activation of ERK1/2 and NF-κB [10,12,32] .…”

Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways

“…diabetes; mitochondria; apoptosis THE PATHOGENIC MECHANISMS by which persistent hyperglycemia and dyslipidemia in diabetes adversely affect the coronary vasculature are well characterized (21), but the mechanisms by which diabetes creates a progressively degenerative state within the myocardium are not as clear. Recently, investigators have focused on the role of myocardial cell death because of the increasing number of studies demonstrating high levels of apoptotic and necrotic cardiomyocytes in experimental models of diabetes (4,23,27) and in cardiac tissue from diabetic patients (14,25,37). Signals initiating myocardial cell death originate from intrinsic (e.g., mitochondria) and extrinsic (e.g., neurohumoral factors) sources (30).…”

“…Importantly, a role for mitochondrial-mediated apoptosis in the etiology of diabetic cardiomyopathy has been clearly established in experimental models (4,12,28,52,56), although evidence is lacking in humans. Moreover, much remains to be understood about the relationship between hyperglycemia and apoptosis in the diabetic heart.…”

Avances en la etiopatogenia de la hipertensión arterial: actualización en la investigación preclínica

“…Asociación entre polimorfismos y aterosclerosis en pacientes con DM2 40---42 Plaquetas Plaquetas circulantes «disfuncionantes» durante la fase aguda de un síndrome coronario agudo. Aumento de la expresión de la PMCA4 en pacientes hipertensos 43---45 Metabolismo energético Nuevos avances en aneurisma y ventrículo izquierdo de SHR 46,47 DM2 y glitazonas Fibrosis y apoptosis miocárdica atenuados por los agonistas de los PPAR-␣ 48,49 Antialdosterónicos Reducen el procesos fibrótico e inflamatorio en el riñón 51 Quercetina Previene la nefrotoxicidad inducida por antitumorales 52 COX-2 Función renal alterada cuando el número de nefronas está disminuido y existe un aumento en la ingesta proteica 53,54 la insulina plasmática, y por consiguiente la resistencia a la insulina 30 . Aunque tales efectos antioxidantes, antihipertensivos y beneficiosos en la acción insulínica y la función endotelial de estos derivados del chocolate se han documentado en varios estudios, aún queda por consensuarlos en estudios en humanos con un gran número de sujetos.…”

“…Los resultados indican que la fibrosis y la apoptosis miocárdica son características de la diabetes mellitus tipo 1 hipertensa crónica. Sin embargo, la inflamación no parece ser relevante en estos estadios de la enfermedad 48 . Estos datos sugieren que la identificación de nuevos factores mediante proteómica podrían desempeñar un papel importante en estos procesos y por ello, estrategias farmacéuticas dirigidas hacia la modulación de estas moléculas podrían suponer una mejora para este tipo de pacientes.…”