Project description:Background: Cardiac macrophages have been implicated in myocardial repair following myocardial infarction (MI), yet their therapeutic potential in ischemic cardiomyopathy (ICM) remains limited by an incomplete understanding of their molecular regulation. CD163 is highly expressed in these macrophages, yet its functional role in regulating post-MI cardiac repair remains unknown. Methods: A cross-sectional clinical study was conducted to assess the association between circulating soluble CD163 concentration and heart failure due to ICM. To investigate the functional contribution of CD163 in ICM, Wild-type (WT) and Cd163/ mice were subjected to permanent ligation of the left anterior descending coronary artery. Single-cell RNA sequencing was employed to analyze transcriptional changes in cardiac immune cells. Recombinant osteopontin (OPN) and CD163 were administered to assess their therapeutic effect in Cd163/ mice. Results: Circulating soluble CD163 levels were markedly elevated in patients with ICM-induced heart failure compared with individuals without heart failure (median difference 34.5 ng/mL, IQR 13.6–54.6 ng/mL, P = 0.002) and showed a positive correlation with the extent of systolic dysfunction and left ventricular dilation. Cd163/ mice displayed aggravated left ventricular systolic dysfunction, reduced ejection fraction and fractional shortening, impaired myocardial strain, and reduced relative wall thickness post-MI. Recombinant CD163 protein could reverse systolic dysfunction and left ventricular dilation in Cd163/ mice after MI. CD163 was predominantly expressed in CCR2⁻ resident cardiac macrophages, and CD163 deficiency altered transcriptional programs of macrophages without affecting their polarization status, with enrichment in cytokine signaling and extracellular matrix-related pathways. Spp1 (OPN) expression was significantly downregulated in Cd163/ hearts under both sham and MI conditions. Administration of recombinant OPN improved systolic function, reduced ventricular dilation, decreased fibrotic scar size, and restored the elastin-to-collagen ratio in Cd163/ mice. Conclusions: In cardiac macrophages, CD163 contributes to post-myocardial infarction repair by upregulating OPN expression, which in turn helps maintain systolic function.

Project description:Impaired myocardial contractile function is a hallmark of heart failure (HF) which may present under resting conditions and/or during physiological stress. Previous studies reported that high fat feeding in HF is associated with improved myocardial contractile function at baseline. Our goal was to determine whether myocardial function is compromised in response to physiological stress and to evaluate the global gene expression profile of rats fed high dietary fat following infarction. Male Wistar rats underwent ligation or sham surgery and were fed normal (10% kcal fat) (SHAM+NC, HF+NC) or high fat (60% kcal saturated fat) (SHAM+SAT, HF+SAT) for 8 weeks. Myocardial contractile function was assessed using a Millar pressure-volume (PV) conductance catheter at baseline, during inferior vena caval occlusions and dobutamine (DOB) stress. Steady state indices of systolic function, left ventricular (LV)+dP/dtmax, stroke work and maximal power were increased in HF+SAT vs HF+NC; HF+NC were reduced vs SHAM+NC. Preload-recruitable measures of contractility [end systolic PV relationship, maximal elastance, preload recruitable SW and peak+dP/dtmax to end diastolic volume] were decreased in HF+NC but not HF+SAT. β-adrenergic responsiveness (delta-LV+dP/dtmax and delta-cardiac output DOB 0-10 µg•kg-1•min-1) was reduced in HF, but high fat feeding did not further impact contractile reserve in HF. Contractile reserve was reduced by high fat in SHAM+SAT. Microarray gene expression analysis reveals the majority of significantly altered pathways identified to contain multiple gene targets correspond to cell signaling pathways and energy metabolism. These findings suggest that high saturated fat improves myocardial function at rest and during physiological stress in infarcted hearts, but may negatively impact contractile reserve under non-pathological conditions. Furthermore, high fat feeding-induced alterations in gene expression related to energy metabolism and specific signaling pathways reveal promising targets through which high saturated fat potentially mediates cardioprotection in heart failure/LV dysfunction. Comparison of gene expression in heart failure or sham surgery hearts exposed to saturated or normal diets. Male Wistar rats (300-350g) were maintained on a reverse light-dark cycle and all procedures were done 3-6 hours into the dark phase cycle to synchronize with the normal active state of the rodents. Rats were randomly assigned to receive either a sham-operation (SH) or coronary ligation to induce cardiac dysfunction (HF). Heart failure was induced by ligating the left main coronary artery. Following surgery, rats were immediately fed either a normal rodent chow (NC) or a high saturated fat chow (SAT) with 60% caloric content derived from fat (25% palmitic, 33% stearic, 33% oleic acid, Research Diets).

Project description:Impaired myocardial contractile function is a hallmark of heart failure (HF) which may present under resting conditions and/or during physiological stress. Previous studies reported that high fat feeding in HF is associated with improved myocardial contractile function at baseline. Our goal was to determine whether myocardial function is compromised in response to physiological stress and to evaluate the global gene expression profile of rats fed high dietary fat following infarction. Male Wistar rats underwent ligation or sham surgery and were fed normal (10% kcal fat) (SHAM+NC, HF+NC) or high fat (60% kcal saturated fat) (SHAM+SAT, HF+SAT) for 8 weeks. Myocardial contractile function was assessed using a Millar pressure-volume (PV) conductance catheter at baseline, during inferior vena caval occlusions and dobutamine (DOB) stress. Steady state indices of systolic function, left ventricular (LV)+dP/dtmax, stroke work and maximal power were increased in HF+SAT vs HF+NC; HF+NC were reduced vs SHAM+NC. Preload-recruitable measures of contractility [end systolic PV relationship, maximal elastance, preload recruitable SW and peak+dP/dtmax to end diastolic volume] were decreased in HF+NC but not HF+SAT. β-adrenergic responsiveness (delta-LV+dP/dtmax and delta-cardiac output DOB 0-10 µg•kg-1•min-1) was reduced in HF, but high fat feeding did not further impact contractile reserve in HF. Contractile reserve was reduced by high fat in SHAM+SAT. Microarray gene expression analysis reveals the majority of significantly altered pathways identified to contain multiple gene targets correspond to cell signaling pathways and energy metabolism. These findings suggest that high saturated fat improves myocardial function at rest and during physiological stress in infarcted hearts, but may negatively impact contractile reserve under non-pathological conditions. Furthermore, high fat feeding-induced alterations in gene expression related to energy metabolism and specific signaling pathways reveal promising targets through which high saturated fat potentially mediates cardioprotection in heart failure/LV dysfunction.

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