Coronary heart diseases (CHD) are the leading cause of mortality and morbidity in the United States. Interestingly, one-third of patients with CHD do not develop cardiac infarction even though they had coronary artery occlusion because the developed collateral artery bypassed the stenosis. Thus, stimulation of coronary vascular growth would offer a prophylactic treatment that could reduce the incidence of sudden death and myocardial infarction. In the recent past, we successfully developed a strategy to reprogram cells into a progenitor-like state (avoiding complications of pluripotency, e.g., teratoma formation) and have found that induced vascular progenitor cells (iVPCs), reprogrammed from endothelial cells, greatly enhanced coronary collateral growth in normal lean rats. However, iVPCs failed to induce coronary collateral growth in a rat model of the metabolic syndrome, Zucker Obese Fatty (ZOF) rats, characterized by obesity, insulin resistance, mild hypertension, and impaired coronary collateral growth. To delineate the mechanisms of why iVPCs were so effective in stimulating coronary collateralgrowthinleanrats,butnotobesefattyrats,weinitiatedstudiestounderstand molecular mechanisms that underscore these differences and to understand the impact of the milieu occurring in a model of metabolic syndrome. We will also develop a progenitor cells more resistant to oxidative stress from vascular smooth muscle (smVPCs) and study if smVPCs augment collateral growth in the ZOF rats and why smVPCs produce a better response under same conditions. Understanding these ?whys? may overcome the present impasse in realizing the potential of therapeutic angiogenesis. We also developed a murine model of coronary collateral growth which enableweusetheinducibletransgenicandknockoutmicetostudytheimportantgenes temporally.Thesesoundsexploring,butwewilluseGDF11andmiR21astwoexamples tostudythekeytargetgenes/signalingtostimulatecoronarycollateralgrowth.
Relevance: Patients with metabolic syndrome (a condition characterized by abnormal obesity, hypertriglyceridemia,insulinresistanceandhyperinsulinemia)havehigherriskofischemiaheartdiseasesand near 30~40% of these patients show little or no coronary collateral growth. Importantly, patients with well- developed coronary collaterals have a better prognosis in recovering from a myocardial infarction than those withpoorlydevelopedcollaterals.Thecurrentproposaltostudythemechanismofimpairedcoronarycollateral growth and stimulate coronary collateral growth in rat model of obesity and insulin resistance will establish therapeutic strategies that stimulate coronary collateral growth in a pre-clinical model characterized by poor collateralizationintheheart.
|Jamaiyar, Anurag; Juguilon, Cody; Dong, Feng et al. (2018) Cardioprotection during Ischemia by Coronary Collateral Growth. Am J Physiol Heart Circ Physiol :|
|Jamaiyar, A; Wan, W; Janota, D M et al. (2017) The versatility and paradox of GDF 11. Pharmacol Ther 175:28-34|