Cardiovascular Complications Associated with Pulmonary Hypertension and Diabetes

Right Heart Failure

Right-sided heart failure (RHF) is a converging manifestation of pulmonary hypertension (PH), regardless of the etiology, when the heart loses its ability to pump blood efficiently. Typically, higher resistance in the pulmonary arteries is associated with a greater risk of worsening right heart dysfunction. Other common causes of RHF include left-sided heart failure and lung diseases such as chronic bronchitis and emphysema, congenital heart disease, clots in pulmonary arteries and heart valve disease. Symptoms associated with RHF include shortness-of-breath, fatigue, swelling, weakness, palpitations and, at advanced stages, multi-organ (such as liver, kidney) failure and fainting. At the University of Arizona Health Sciences (UAHS), we have a spectrum of ongoing research led by multiple nationally renowned investigators to better understand right heart dysfunction and pulmonary vascular disease. Basic and translational research using molecular, cellular, and animal models put us at the leading edge of scientific discovery. Simultaneously, clinical research in patients is currently elucidating causes and ways to stratify patients with RHF and PH. From association of RHF with novel genetic conditions to the presence of diabetes mellitus, UAHS is at the forefront to develop novel pathways that may help to discover new therapeutic targets for RHF and PH.

Coronary and Pulmonary Vascular Endothelial Dysfunction in Diabetes

Cardiopulmonary and vascular complications associated with diabetes are major contributors to mortality of patients with diabetes. Dr. Ayako Makino’s laboratory specializes in research centered on the modulation of endothelium function in pathological state. Vascular endothelial cells play a critical role in vascular function, as they are involved in regulation of vascular tone, formation of new vessels, and serving as an anticoagulant barrier between blood and the vascular wall. Many cardiovascular diseases result in endothelial cell damage and subsequent vascular complications. Here at the University of Arizona, we investigate the cellular and molecular mechanisms of coronary and pulmonary vascular endothelial dysfunction in diabetes. We utilize a variety of techniques including isolation of primary coronary and pulmonary endothelial cells, dissection of mouse coronary and pulmonary vessels to perform isometric tension experiment, in vivo measurement of cardiac functions using the Millar system, electrophysiological experiments and advanced molecular biological experiments. In addition, we perform gene transfection to restore endothelial functions in ex vivo and in vivo. The recent (2015) research findings in Dr. Makino’s program are briefly described here:

OGA is involved in coronary endothelial cell dysfunction in type 1 diabetic mice

Diagram courtesy of Ayako MakinoIncreased O-linked N-acetylglucosamine (O-GlcNAc) protein modification is one of the central pathogenic features of diabetes. The enzyme β-N-acetylglucosaminidase (O-GlcNAcase or OGA) catalyzes the reduction of protein O-GlcNAcylation. We used tetracycline-inducible EC-specific OGA transgenic mice and OGA was induced by Doxycycline (DOX) administration in the streptozotocin-induced type 1 diabetic mice.

In diabetic mice, OGA protein expression was significantly decreased and the levels of protein O-GlcNAcylation was increased in mouse coronary endothelial cells (MCECs) compared to control mice. OGA overexpression significantly decreased the levels of protein O-GlcNAcylation in MCECs in DOX-treated diabetic mice compared with diabetic mice without DOX treatment. Capillary density in the left ventricle was significantly decreased in diabetes, while OGA overexpression increased capillary density to the control level. Endothelium-dependent relaxation (EDR) was significantly attenuated in diabetic coronary arteries compared to control, whereas OGA overexpression restored EDR without changing EC-independent relaxation. Furthermore, we found that connexin 40 could be the potential target of O-GlcNAcylation that regulates the endothelial functions in diabetes. This study was selected for “APSselect” in the American Journal of Physiology - Cell Physiology (published in Am. J. Physiol. Cell Physiol. 309(9):C593-C599, 2015).

Role of SGLT inhibitors in pulmonary and coronary vascular relaxation

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral drugs for the treatment of type 2 diabetes and they reduce plasma blood glucose levels by inhibiting renal glucose reabsorption. However, there are no data of microvascular or cardiovascular outcomes. In this study, we investigated the role of SGLT inhibitors in vascular function with a focus on the transporter subtypes. We examined the expression levels of SGLT 1-6 between pulmonary and coronary arterial smooth muscle cells (PASMCs and CASMCs) and endothelial cells collected from human and mouse and found that SGLT1 and 4 were expressed more in PASMCs than CASMCs, while SGLT3 expression levels were less in PASMCs than CASMCs in mice. In human samples, SGLT1 was detected in PASMCs, but not in CASMCs. We also examined how SGLT inhibitors attenuate nitric oxide (NO) dependent vascular relaxation in PASMCs. Patch-clamp experiments revealed that SGLT2 inhibitors inhibit NO-induced K+ channel opening and membrane hyperpolarization and they subsequently attenuate NO-dependent vascular relaxation in pulmonary arteries. This finding is published in the American Journal of Physiology - Cell Physiology (Am. J. Physiol. Cell Physiol. 309(9):L1027-L1036, 2015).

Mitochondrial ion channels in metabolic disease (review article)

Mitochondria are cellular organelles responsible for energy production and involved in cell signaling pathways such as cell apoptosis. Many ion channels reside in mitochondrial inner or outer membranes and they are integral in the function of mitochondria. There is increasing evidence that dysregulation of mitochondrial ion channels is implicated in the development and progression of cardiovascular diseases. In this article, we reviewed the role of mitochondrial ion channels in metabolic diseases [in Ion Channels in Vascular Diseases (Book Chapter). In Press].