P66Distinct intracellular signaling pathways in pressure overload and/or diabetes mellitus lead to different myocardial structural and functional phenotypes

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Diastolic heart failure (DHF) accounts for ∼50% of HF cases and represents a growing problem. Its pathophysiology is ascribed to impaired relaxation or increased myocardial stiffness. Often, chronic pressure-overload (PO) and diabetes mellitus (DM) lead to DHF. Moreover, hypertension is more prevalent among the diabetic population and exacerbates the extent of diabetic cardiomyopathy. Even so, functional and structural cardiac consequences of combined PO and DM are still unclear. The present study aimed to characterize myocardial morphological and functional changes induced by DM and/or PO as well as its underlying mechanisms.

PO was performed in Wistar-male rats by supra-renal aortic banding. After six-weeks, diabetes was induced by streptozotocin (65 mg/kg, ip) resulting in four groups: SHAM, banding (BA), diabetic (DM) and diabetic-banding (DB). Six weeks later, hemodynamic study was performed to evaluate cardiac performance. Samples were collected for histology, molecular studies and force measurement in isolated skinned cardiomyocytes.

Chronic PO increased LV hypertrophy (enlarged cardiomyocyte diameter) myofilament active force and Ca2+ sensitivity as well as phosphorylation of myofilamentary protein (MLC-2, MyBP-C) and hypertrophic and insulin signaling pathways proteins (Erk, Akt). At the extracellular matrix level, interstitial fibrosis and pro-MMP-2 e MMP-9 activity were increased. In vivo, contractility (LV peak systolic pressure (LV-ESP) and maximal LV wall stress (LV-Wstress) was increased and correlated positively with Factive, while relaxation was impaired. DM increased cardiomyocyte diameter, the expression of inflammatory (TNF-α) and apoptosis markers (Bax/Bcl-2). At the extracellular matrix level, diabetic animals displayed augmented myocardial fibrosis and AGEs deposition. In vivo, these abnormalities resulted in increased stiffness confirmed by the higher values of LV end-diastolic-pressure and end-diastolic pressure–volume relation. Furthermore, diabetic animals displayed lower contractility (end-systolic pressure–volume relation (ESPVR), expression of MHC-α/MHC-β and, as expected, lower activation of insulin signaling pathways (Akt phosphorylation levels).

DB animals combined overload-induced relaxation abnormalities and diabetes-induced stiffness. Additionally showed further pulmonary congestion. We conclude that DM and PO lead to distinct diastolic dysfunction phenotypes: while diabetes promoted myocardial stiffening, pressure overload impaired relaxation. The association of these damages accelerates the progression of DHF.

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