ABSTRACT
SUBRINA JESMIN, ARIFUR RAHMAN, ABDULLAH AL MAMUN, FARZANA SOHAEL, SHAMIMA AKTER, YOSHIO IWASHIMA, NOBUTAKE SHIMOJO, NAOTO YAMAGUCHI, MICHIAKI HIROE, TARO MIZUTANI, and MASAO MOROI
Abstract ................................................................................................. 449 12.1 Introduction ................................................................................ 450 12.2 Microcirculatory Disturbances in Diabetic Heart ...................... 451 12.3 Diabetes Mellitus and Coronary Collaterization ........................ 454 12.4 Role of Vascular Endothelial Growth Factor (VEGF) in
Coronary Microcirculation in Diabetes ..................................... 455 12.5 Therapeutics to Restore Cardiac VEGF Level in Diabetes ........ 459 12.6 Pharmacological Approaches to Restore Coronary
Microcirculation and Cardiac VEGF Signaling in Diabetes ...... 460 12.7 Endothelin Blocker and Diabetic Cardiac Microcirculation ...... 460
12.8 Experimental Animals Used ..................................................... 461 12.9 Expression of VEGF and its Receptors .................................... 462
12.10 VEGF Signaling Pathways ...................................................... 462 12.11 Morphological Data ................................................................. 462 12.12 Assesment of Cardiac Functions by Echocardiography ........... 464 12.13 Statins and Cardiac VEGF Signaling in Diabetes .................... 466 12.14 Diabetic Cardiac Complication and Gene Therapy ................ 468 12.15 Organ Specific Expression and Role of VEGF in
Diabetic Complicatio ............................................................... 470 12.16 Our Proposed Therapeutic Model for Diabetic
Microvascular Complications .................................................. 471 12.17 Conclusion ............................................................................... 472 Keywords .............................................................................................. 473 Acknowledgement ................................................................................ 473 Abbreviation ......................................................................................... 473 References ............................................................................................. 474
ABSTRACT
The microcirculatory disturbances in diabetic heart and the consequences: Abnormal coronary microcirculation is an integral part of the pathophysiology of both ischemic and nonischemic cardiomyopathies, and is not only a unique tool to aid diagnosis and determination of prognosis, but also to guide interventions and management. Microcirculatory dysfunction is well documented, even in the pre-diabetic state; it involves alterations in coronary circulation, globally as well as regionally, even in absence of large coronary obstructive lesions. Authors background to Diabetic coronary microcirculation research: they and other research groups found that disturbances in the levels of microcirculatory growth factor are central key in the development and progression of diabetic cardiomyopathy. Most recently their research group has focused on findings ways of correcting altered microcirculation in diabetic heart. Vascular endothelial growth factor (VEGF), a major vascular factor involved in all three types of vascular growth (angiogenesis, arteriogenesis and atherogenesis), acts as a central trigger myocardium leading to all the structural and functional changes in diabetic myocardium, such as decreased abnormal coronary collaterals development, abnormalities in coronary flow reserve, coronary microvascular rarefaction, myocardial hypertrophy, myocyte death, and varying degrees of fibrosis, impaired myocardial function, defective cardiac progenitor cell growth, and myocyte formation. Thus, a diagnostic tool based on coronary microcirculation in diabetic subjects and the therapeutic approach for the restoration of VEGF, as well as coronary microcirculation, is crucial for the prevention and treatment of diabetic cardiac complication. They previously have used pharmacological intervention in diabetic model and systematically assessed the effects of drug on the development and progression of various complications in diabetes including diabetic cardiomyopathy. They found that endothelin (ET) blockade is effective, systematically, to prevent the development, and progression of various diabetic complications including those localized in the heart through the modification of respective microcirculation and the associated signal transduction. Systemic administration of ET blocker prevents diabetic cardiomyopathy through restoration of VEGF, prevents diabetesmediated erectile dysfunction through VEGF upregulation, and prevents
the development of diabetic retinopathy and nephropathy through VEGF inhibition. Their ongoing study uses statin and has beneficial effect on heart.
