Macrophage Depletion in Hypertensive Rats Accelerates Development of Cardiomyopathy

Abstract

Inflammation contributes to the process of ventricular remodeling after acute myocardial injury. To investigate the role of macrophages in the chronic process of cardiac remodeling, they were selectively depleted by intravenous administration of liposomal clodronate in heart failure-prone hypertensive Ren-2 rats from the age of 7 until 13 weeks. Plain liposomes were used for comparison. Liposomal clodronate treatment reduced the number of blood monocytes and decreased the number of macrophages in the myocardium. Compared to plain liposomes, liposomal clodronate treatment rapidly worsened left ventricular ejection function in hypertensive rats. Liposomal clodronatetreated Ren-2 rat hearts showed areas of myocyte loss with abundant inflammatory cell infiltration, predominantly comprising CD4 positive T lymphocytes. The current study showed that lack of macrophages was associated with earlier development of myocardial dysfunction in hypertensive rats. Modulation of macrophage function may be of value in the evolution of cardiomyopathy.

Immune Cell and Other Noncardiomyocyte Regulation of Cardiac Hypertrophy and Remodeling

“…Although no differences in cardiac hypertrophy were observed, depletion with clodronate liposomes resulted in cardiac dysfunction with decreased ejection fraction and fractional shortening, and increased end-diastolic volume. 43 Greater cardiomyocyte loss and abundant increases in CD4 + T cells were present in macrophage-depleted rats, suggesting that macrophages are important in coordinating T cell responses.…”

Chronic Inflammation Links Cardiovascular, Metabolic and Renal Diseases

“…55 By contrast, macrophage depletion using liposomal clodronate induces abundant infiltration of inflammatory cells, predominantly CD4 + lymphocytes, and worsens cardiac dysfunction in hypertensive rats harboring the mouse renin gene (Ren2). 56 This suggests macrophages exert a protective effect against cardiac dysfunction induced by hypertension. These results also indicate that macrophages have multiple functions during the development of cardiac hypertrophy and heart failure.…”

Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

“…94 In response to pressure overload after TAC, Ly6c lo cardiac macrophages are specifically increased, whereas Ly6c hi macrophages remain unchanged in number. 95 Administration of clodronate liposome into hypertensive Ren-2 rats to deplete cardiac macrophages led to a decrease in cardiac contractile function in the early period, 96 suggesting that cardiac macrophages are crucial for cardioprotection against pressure overload. In contrast, macrophage-specific mineralocorticoid receptor knockout mice showed blunted cardiac hypertrophy and fibrosis after aortic constriction, 97 or administration of deoxycorticosterone/salt or L-NAME/Ang II.…”