Molecular Cardiology Research Institute (MCRI)

20 years of scientific discovery

For the past 20 years, the investigators and research teams of the Molecular Cardiology Research Institute (MCRI) have continually translated basic findings into new clinical strategies for the diagnosis and treatment of cardiovascular disease.

Some of our scientific accomplishments over the past 20 years include:

• (1998) Blood vessels respond directly to hormones. MCRI Investigators first discovered in the 1990s that the heart and blood vessels have molecular receptors needed to respond to the hormone estrogen. This discovery pioneered the field of estrogen action on the cardiovascular system and is leading to safer and more effective hormone therapies for women's heart health.
• (2004) Blood vessel constriction can directly cause high blood pressure. Previously high blood pressure was thought to be exclusively a kidney problem however, in the early 2000s, MCRI investigators made several ground breaking discoveries demonstrating that it can result from a primary defect in blood vessel function, leading to new targets for blood pressure control. 
• (2002) MCRI investigators have made substantial advances in understanding how the blood vessel and the platelet interact to prevent blood clotting in the healthy vessel and lead to blood clotting when the vessel is diseased. These findings contributed to our current understanding of the cause of heart attacks and strokes and are being translated into new treatments.  
• (2003-2018) Multiple MCRI Investigators spanning 2 decades have made substantial contributions to our understanding of the mechanisms leading to the number one cause of hospitalization – heart failure. These discoveries identified multiple new drug targets that are being developed for heart failure treatment and a discovery that white blood cells contribute to heart failure and may provide a potential new strategy to improve the heart function in the failing heart.
• (2006/2017) MCRI efforts to understand how cancer therapy causes heart and vascular disease are leading to safer treatments for cancer patients. Work in the mid 2000s explored how cancer therapy causes heart failure. Recent studies are uncovering how the new targeted cancer treatments cause blood vessel dysfunction leading to heart attacks and strokes and how to prevent those adverse outcomes in cancer survivors.
• (2008/2016) Small noncoding RNAs play key role in blood vessel function and contribute to hypertension as we age: In 2008, MCRI investigators discovered how microRNAs mature in blood vessel cells and can regulate blood vessel function. In 2016, one of these microRNAs was identified as contributing to blood vessel constriction with aging. High blood pressure affects 80 percent of people over the age of 80. MicroRNA levels in the serum of older people are now being evaluated as biomarkers to tailor high blood pressure treatment.
• (2013) MCRI Investigators recently discovered that, in the setting of a heart attack with a blocked coronary artery, reducing the work of the heart by unloading it with a pump while delaying opening the heart artery activates a heart protection program and reduces heart attack size. This paradigm-shifting approach is now being tested in a multicenter clinical trial in people having heart attacks.
• (2016) Establishment of the MCRI biobank is allowing MCRI investigators to advance our understanding of heart and blood vessel disease by working with the physicians that care for unique patient populations. For example, by studying tissue, blood samples, and DNA from the large population of patients treated at Tufts Medical Center with hypertrophic cardiomyopathy, MCRI investigators have identified new genes that modify the severity of heart disease in patients with this genetic condition.
• (2017) MCRI investigators are working with engineers and biotechnology companies to develop better devices and drugs to treat heart failure. Drugs are being tested in the MCRI animal physiology core that may improve heart-pumping function and decrease heart scarring to alleviate heart failure. MCRI inventions also recently lead to the formation of a company to develop novel heart failure devices.
• (2018) Obesity is a growing epidemic and contributes to blood vessel disease that leads to heart attacks and strokes. Investigators in the MCRI recently discovered that female and male blood vessels respond to obesity in completely different ways. The cause of the blood vessel dysfunction depended not only on the sex but also whether there was high blood sugar or high cholesterol along with obesity. This suggests that treatments to prevent the adverse effects of the obesity epidemic may need to be personalized based on sex as well as other risk factors in each individual patient.

1998 -

Journal of Clinical Investigation
Growth Factor Activation of the Estrogen Receptor in Vascular Cells Occurs via a Mitrogen-activated Protein Kinase- independent Pathway

1999 - 

Science
Regulation of Myosis Phosphatase by a Specific Interaction with CGMP- Dependant Protein Kinase

2001 -

Journal of Clinical Investigation
A complex role for the progesterone receptor in the response to vascular injur

2002 -

Nature Medicine
Pepducin-based intervention of thrombin-receptor signal and systemic platelet activation

Science
Abnormal Vascular Function and Hypertension in Mice Deficient in Estrogen receptors

PNAS
Activation and inhibiation of G protein-coupled receptors by cell-penetrating membrane-tethered peptides

2003 -

PNAS
Stabilization of B-catenin by a Wnt- independent mechanism regulates cardiomyocyte growth

2004- 

Nature Medicine
Regulator of G-protein signaling- 2 mediates vascular smooth muscle relaxation and blood pressure

2005 - 

Circulation Research
Anglotensin II and Aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells

2006 - 

Nature Medicine
Cardiotoxicity of the cancer therapeutic agent imatinib mesylate

2008- 

Nature
SMAD proteins control DROSHA-mediated microRNA maturation

PNAS
High blood pressure arising from a defect in vascular function

Journal of Clinical investigation
Deletion of GSK-3B in mice leads to hypertrophic cardiomyopathy secondary to cardiomyoblast hyperproliferation

2009- 

PNAS
Membrane-tethered ligands are effective probes for exploring class B1 G Protein-coupled receptor function

2012-

Nature Medicine
Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors

Circulation
Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure

2013-

Circulation
Mechanical unloading the left ventricle before coronary reperfusion reduces left ventricular wall stress and myocardial infarct size

2016-

JCI Insight
Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging

MCRI Discoveries: 1998-2018

• (1998) Blood vessels respond directly to hormones. MCRI Investigators first discovered in the 1990s that the heart and blood vessels have molecular receptors needed to respond to the hormone estrogen. This discovery pioneered the field of estrogen action on the cardiovascular system and is leading to safer and more effective hormone therapies for women's heart health.
• (2004) Blood vessel constriction can directly cause high blood pressure. Previously high blood pressure was thought to be exclusively a kidney problem however, in the early 2000s, MCRI investigators made several ground breaking discoveries demonstrating that it can result from a primary defect in blood vessel function, leading to new targets for blood pressure control. 
• (2002) MCRI investigators have made substantial advances in understanding how the blood vessel and the platelet interact to prevent blood clotting in the healthy vessel and lead to blood clotting when the vessel is diseased. These findings contributed to our current understanding of the cause of heart attacks and strokes and are being translated into new treatments.  
• (2003-2018) Multiple MCRI Investigators spanning 2 decades have made substantial contributions to our understanding of the mechanisms leading to the number one cause of hospitalization – heart failure. These discoveries identified multiple new drug targets that are being developed for heart failure treatment and a discovery that white blood cells contribute to heart failure and may provide a potential new strategy to improve the heart function in the failing heart.
• (2006/2017) MCRI efforts to understand how cancer therapy causes heart and vascular disease are leading to safer treatments for cancer patients. Work in the mid 2000s explored how cancer therapy causes heart failure. Recent studies are uncovering how the new targeted cancer treatments cause blood vessel dysfunction leading to heart attacks and strokes and how to prevent those adverse outcomes in cancer survivors.
• (2008/2016) Small noncoding RNAs play key role in blood vessel function and contribute to hypertension as we age: In 2008, MCRI investigators discovered how microRNAs mature in blood vessel cells and can regulate blood vessel function. In 2016, one of these microRNAs was identified as contributing to blood vessel constriction with aging. High blood pressure affects 80 percent of people over the age of 80. MicroRNA levels in the serum of older people are now being evaluated as biomarkers to tailor high blood pressure treatment.
• (2013) MCRI Investigators recently discovered that, in the setting of a heart attack with a blocked coronary artery, reducing the work of the heart by unloading it with a pump while delaying opening the heart artery activates a heart protection program and reduces heart attack size. This paradigm-shifting approach is now being tested in a multicenter clinical trial in people having heart attacks.
• (2016) Establishment of the MCRI biobank is allowing MCRI investigators to advance our understanding of heart and blood vessel disease by working with the physicians that care for unique patient populations. For example, by studying tissue, blood samples, and DNA from the large population of patients treated at Tufts Medical Center with hypertrophic cardiomyopathy, MCRI investigators have identified new genes that modify the severity of heart disease in patients with this genetic condition.
• (2017) MCRI investigators are working with engineers and biotechnology companies to develop better devices and drugs to treat heart failure. Drugs are being tested in the MCRI animal physiology core that may improve heart-pumping function and decrease heart scarring to alleviate heart failure. MCRI inventions also recently lead to the formation of a company to develop novel heart failure devices.
• (2018) Obesity is a growing epidemic and contributes to blood vessel disease that leads to heart attacks and strokes. Investigators in the MCRI recently discovered that female and male blood vessels respond to obesity in completely different ways. The cause of the blood vessel dysfunction depended not only on the sex but also whether there was high blood sugar or high cholesterol along with obesity. This suggests that treatments to prevent the adverse effects of the obesity epidemic may need to be personalized based on sex as well as other risk factors in each individual patient.

 

 

  • Research conducted by MCRI investigators on the ways in which hormones like estrogen act directly on the blood vessels and heart have altered how scientists and clinicians think about and design hormone replacement therapies and has led to new approaches in the pharmaceutical industry to develop more effective and safer approaches to medicines for women's health.
  • Investigators within the MCRI recently identified a protein called striatin that plays a key role in allowing the estrogen receptor to interact with and bind to other proteins that mediate the effects of estrogen in cells in the blood vessel and other tissues.
  • MCRI investigators have been studying how blood vessels relax and contract for nearly 20 years. MCRI investigators have discovered several important mechanisms of vascular smooth muscle relaxation in response to nitrovasodilators. These mechanisms involve, in many cases, a critical molecule that regulates vessel tone, called cyclic GMP-dependent protein Kinase I (PKGI). New drugs will likely be developed using information about PKGI in blood vessels.
  • MCRI researchers discovered a new regulatory molecule for blood vessel relaxation, called Myosin Phosphatase-rho Interacting Protein (M-RIP) which has at least two important targeting functions.  It localizes the myosin phosphatase complex to the actinomyosin contractile complex to dephosphorylate myosin, and it links the RhoA/ROCK pathway with myosin phosphatase, allowing RhoA/ROCK to inhibit myosin phosphatase activity in response to vasoconstrictors.
  • Researchers within the MCRI have discovered that a specific class of protein hormones, named BMPs, prevents smooth muscle cells from growing too much and losing their ability to regulate blood pressure. This work continues with study of the requirement of BMPs for maintenance of vascular smooth cell function and the molecular mechanism by which BMPs act.
  • Recent studies have implicated a potential role of Toll-like receptors (TLRs), receptors that are expressed by immune cells and activated by microbial products, in the pathogenesis of atherosclerosis.   MCRI researchers have shown that vascular smooth muscle cells also express several TLRs, and that activation of these receptors upon exposure to microbial products elicits dramatic changes in smooth muscle cell phenotype, including cell proliferation and synthesis of chemokines, phenotypic changes similar to those that contribute to vascular disease.