Macrophage to Myofibroblast Transition Promotes Hypertension-Induced Cardiac Diastolic Dysfunction
Authors: Mora Christoph , Liu Yunmeng , Deck Katherine , Benson Lance , Guo Yunping , Mu Shengyu 
Published: May 2024

Cardiac diastolic dysfunction is a pathological continuum of hypertension eventually leading to heart failure—which is responsible for ~13% of all deaths in the United States. A hallmark of this disease is cardiac fibrotic remodeling, in which excessive extracellular matrix components are deposited into the myocardium. Recent studies have shown the novel ability of macrophages to differentiate into a fibrotic myofibroblast-like phenotype—termed macrophage to myofibroblast transition (MMT). This phenomenon has been implicated in renal fibrosis but, has not been investigated in the heart during hypertension or diastolic dysfunction. Therefore, we hypothesize that MMT plays a causal role in cardiac fibrotic remodeling in hypertension, promoting diastolic dysfunction. As such, we seek to investigate the prevalence of myofibroblast-transitioned macrophages in the heart, as well as determine the gravity of MMT-mediated fibrotic cardiac remodeling. To understand the pathological progression of hypertension to diastolic dysfunction, we utilized the classic DOCA + NaCl model of hypertension in C57BL/6 mice. This investigation is multi-pronged, in that, we seek to gauge diastolic function in vivo, as well as investigate the microenvironment of the heart in primary in vitro experiments. To achieve this, we employ echocardiography and direct left ventricular pressure and volume measurements to determine the progression of hypertension to diastolic dysfunction in the adult mouse heart. For primary in vitro analyses, mouse hearts were isolated and digested, and leukocytes were isolated by Percoll gradient. Cells were stained with α-SMA (myofibroblast) and CD68 (monocyte/macrophage). Finally, the deposition of fibrotic collagen was assessed by both Masson’s trichrome and picrosirius red tissue stains. Mice were subjected to DOCA + salt to induce hypertension. Ten days after this treatment, the left ventricular pressure change as a function of time was measured in the left ventricle. This analysis revealed degraded heart function, realized by a significant decrease in -dp/dt as soon as ten days following the onset of hypertension. Following, another cohort of hypertensive WT mouse hearts was isolated for staining. The results of these assays revealed increased cardiac fibrosis in the hearts of hypertensive mice—likely contributing to the deficit in cardiac function. Finally, in addition to this, flow cytometric analyses of isolated cardiac leukocytes revealed that hypertensive mice had a significant increase in the α-SMA+/CD68+ population of cells in the hypertensive mouse heart, implicating MMT in the rapid pathological progression of hypertension to diastolic dysfunction. These results characterize the presence of MMT cells in the hypertensive mouse heart. Furthermore, the increase of myofibroblast transition is accompanied by decreased cardiac diastolic function and enhanced fibrotic remodeling in the heart—alluding to the role of MMT in the pathological progression of hypertension to diastolic dysfunction. Future efforts into this phenomenon involve the real-time progression of hypertension to diastolic dysfunction via echocardiography, as well as a final, definitive measurement of diastolic function by PV loop. Finally, we will employ an angiotensin II model of hypertension to ensure that this phenomenon is encapsulated in other forms of hypertension, rather than just the DOCA + Salt model. We thank our sources of funding:NIG R01-HL146713, AHA 23TPA1076467. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.